Season one began airing Sunday, March 27, 2005 and ended on May 22, 2005. The first season was shortened by the network to nine episodes instead of 14. (The original season finale was "Bring the Pain."). Meredith Grey, the daughter of the once-renowned surgeon Ellis Grey, becomes an intern at the Seattle Grace Hospital. She meets fellow interns Cristina Yang, Isobel "Izzie" Stevens, and George O'Malley who would be her closest friends during the intern program. Other characters include Dr. Miranda Bailey, nicknamed "Nazi" due to her "tough love" capability; Alex Karev, an intern who is not very popular with the others (especially Izzie); and renowned surgeons Dr. Derek Shepherd and Dr. Preston Burke. The chief of surgery is Richard Webber, who was once more than close friends with Meredith's mother. The season chronicles the first few months of the internship program and the day-to-day life of a surgical intern. Recurring plots include Meredith's battle to keep her mother's Alzheimer's disease a secret and her relationship with Dr. Shepherd. Others include George's infatuation with Meredith and a power struggle between Dr. Burke and Dr. Shepherd in the hospital. The season's end introduces Kate Walsh as Dr. Addison Montgomery-Shepherd, Derek's estranged wife. Although for other areas where the season was aired, the season end is Meredith waiting (Season 2, Episode 5).

The second season aired Sunday, September 25, 2005, and ended on May 14 and May 15, 2006 with a three-hour finale spanning both nights. The first season had originally contained 14 episodes, representing ABC's original midseason order for the show. However, it was decided to end the season early because ABC executives wished for the show's first season to end with ABC's Desperate Housewives (which had the timeslot before Grey's Anatomy for the first two seasons). Rather than condensing or throwing out plotlines, Grey's Anatomy producers chose to end the first season with the ninth episode and save the following episodes for the second season. Episodes 10-14 were then held and broadcast as the first five episodes of Season 2. ABC ordered 22 episodes in addition to the five being carried over, bringing the total number of episodes for the second season to 27. Bring the Pain, which aired as the series' 14th episode, has been cited in series creator Shonda Rhimes' blog as having been originally intended as the first season finale. The second season focuses on Meredith and Derek's relationship, which came to an abrupt halt when it was revealed that Derek is married to surgeon Addison Montgomery. Izzie and Alex embark on a relationship of their own (although cut short when Izzie falls for heart patient Denny Duquette), as do Cristina Yang and Preston Burke. Doctor Bailey becomes pregnant, and more is revealed about her personal life. On some of the weeks airing after its highly-watched February 5, 2006 post-Super Bowl episode, the program attracted more viewers than its lead-in, Desperate Housewives. Once the second season ended on May 15, 2006, the show had two previously recurring actors, Sarah Ramirez (Callie Torres) and Eric Dane (Mark Sloan), join the regular cast. The series' opening credit sequence was also dropped by the last half of the second season, replaced by a title card displayed at the end of the first act and credits displayed over the opening of the second act of each episode.

On May 16, 2006, the morning following the close of the second season, ABC announced plans for a third season of Grey's Anatomy to anchor the network's Thursday evening programming, set to air at 9 p.m. ET. ABC first tested the series' potential for Thursday audiences on February 9, 2006, as it aired an encore of the Super Bowl XL-leadout episode titled "It's the End of the World." The following Thursday, February 16, 2006, the network repeated the second part of the story arc, "(As We Know It)." Both airings began at 9:30 p.m. ET, and thus positioned Grey's Anatomy against CBS' CSI: Crime Scene Investigation and Without a Trace, Fox Network's The OC, and NBC's long-running medical drama ER. Solid performance on these nights, with the repeat airings maintaining a strong second-place finish, may have been influential in the fall scheduling decision. The move to Thursdays was viewed as a vote of confidence in the series from ABC, as well as a bid to attract more advertising dollars, since movie studios heavily advertise movies on Thursday evenings for that weekend's box office. The move was cited as one factor for competing network NBC's decision to move its own Studio 60 on the Sunset Strip, originally intended to air Thursdays at 9 p.m. ET. ABC announced on July 18, 2006, that the third season would premiere on September 21, 2006. The series assumed its new Thursday slot on July 6, 2006, as part of a two-hour event featuring a repeat of the pilot episode, "A Hard Day's Night." Throughout July and August, the series aired twice weekly, once in the new Thursday time period, and once in its previous Sunday time period. Grey's Anatomy performed strongly in the show's new timeslot in its season premiere. It was able to snatch away the #1 position from CSI: Crime Scene Investigation during the 9 p.m. hour, bringing in an impressive 25.14 million viewers throughout the hour and a strong 10.9 rating in the vital 18-49 demographic. In comparison, CSI's season premiere earned a competitive 22.04 million total viewership and a 7.5 rating in the 18-49 demographic. The third season ended on May 17, 2007. As the season came to a close, Burke called off his wedding to Cristina at the church, Chief Webber stayed on as the Chief of Surgery, Callie was appointed Chief Resident, and George learned he failed the final intern exam. The relationship between Derek and Meredith, as well as the triangle between Callie, George, and Izzie were left unresolved. Addison decides to start a new life in Los Angeles in the spin-off Private Practice.

The show was renewed for a fourth season, with the first episode airing on September 27, 2007. In the official blog, creator Shonda Rhimes gave a few clues as to plotlines for season four, indicating that Mark Sloan will be given a bigger role and in the aftermath of the finale, events for Derek Shepherd and Cristina Yang will be "interesting to watch." Due to her producing responsibilities on both Grey's and the spin-off, Rhimes assigned the day-to-day showrunning duties to writer and executive producer Krista Vernoff. For the first time in the show's history, many of the series regulars were not returning. Kate Walsh's character was transferred to the Grey's Anatomy spin-off, Private Practice. On June 7, 2007, it was announced that Isaiah Washington's contract had not been renewed. Former Reunion star, Chyler Leigh, guest starred in the final two episodes of season three as Lexie Grey, a new intern and Meredith Grey's younger half-sister. On June 11, 2007, it was announced that Leigh would become a series regular, instead of a 13 episode story arc as previously planned. The character Dr. Erica Hahn (The Silence of the Lambs fame actress Brooke Smith) joined the main cast, reprising her antagonizing role in the season's fifth episode. She replaces Preston Burke as head of Cardiothoracics. Upon her return, she makes Sandra Oh's character, Cristina Yang work harder for her success in Cardiothoracics and initially served as a new love interest for Eric Dane's Mark Sloan. It was reported that a new male character would be introduced. This character would somehow be in "competition" with Dr. Derek Shepherd. Fourth season guest stars included former Gilmore Girls actor Edward Herrmann who appeared in three episodes. Seth Green of Buffy the Vampire Slayer fame guest starred in a two-part episode. Lauren Stamile plays a scrub nurse named Rose, who became a potential love interest for Derek. Dawson's Creek alumnus Joshua Jackson was scheduled to make his return to television in a multi-episode arc as a doctor with his first appearance in the season's eleventh episode. Jackson's appearance was cancelled due to the 2007-2008 Writers Guild of America strike. Kate Walsh returned as Dr. Addison Montgomery on May 1. On February 20, 2008, it was confirmed that Grey's Anatomy would return on April 24, 2008 for five new episodes. Where the Wild Things Are was the first episode shown after the incubation resulted from WGA strike. The double episode finale (Freedom) aired May 22, 2008. It was centered around Meredith having a huge breakthrough with her personal life including Derek and her mother. Derek also realized he continually failed Meredith. Meredith and Derek performed clinical trials on patients with brain tumors. They lost all of their patients except for one whose boyfriend died just before her life saving surgery. After finally succeeding, Meredith finally took a risk and reunited with Derek. Almost all the cast had a kiss, including Meredith and Derek, George and Lexie, Richard and Adele, Alex and Izzie, and, Erica and Callie. To prepare for the lesbian story line, which will continue in season five, Grey's consulted with GLAAD. We also learned about Alex's needy mother and part of his past. After Meredith and Derek's resumption of their relationship, Derek left to break up with Rose, his girlfriend who had come between the two previously.

The fifth season began on September 25, 2008, directly after the third season premiere of Ugly Betty for a two-hour long premiere. (There was the possibility that the production of the fifth season could have been delayed because of the possibility of a Screen Actors Guild strike.) Regular one-hour episodes of the series are expected to begin airing in the U.S. on October 9, 2008, following a preemption due to October 2 coverage of the 2008 Vice Presidential Debate. OK! magazine reported that Katherine Heigl is remaining with Grey's Anatomy. On November 3, 2008 it was announced that Brooke Smith who plays Erica Hahn will be dismissed from the show during the 5th season. Additionally, newcomers Kevin McKidd and Melissa George are being added to the cast. On November 6, 2008, TV Guide reported that Grey's Anatomy will feature a multi-episode crossover arc with spin-off Private Practice in time for February sweeps. So far this season, Meredith and Derek haven't hit many rough patches. Meredith stumbles across her dead mother's diaries. Callie and Erica have a fling; however, Callie has a hard time adjusting to life as a lesbian. She "cheats" on Erica in the on-call room with Mark Sloan. During the episode, Rise Up, Izzie has a minor melt-down when she begins to see Denny everywhere, after meeting the man whose donor heart she stole in order to save Denny during season 2. When Erica learns of Izzie's actions, she insists that everyone should be punished, and plans to report not only Izzie, but the hospital as well, angering not only Chief Webber but Callie as well. Alex and Izzie have also rekindled their romance. Lexie had a crush on George but when he didn't notice, she moved on. Cristina shared a kiss with an army doctor named Owen Hunt (played by Kevin McKidd). A couple episodes later, Hunt was named Head of Trauma. In the most recent episode Cristina shared another kiss with Dr. Owen Hunt.