Season one began its original airing on October 3, 2004 and introduces the four central characters of the show: Susan Mayer, Lynette Scavo, Bree Van de Kamp and Gabrielle Solis, and their families and neighbors on Wisteria Lane. The main mystery of the season is the unexpected suicide of Mary Alice Young, and the involvement of her husband and teenage son in the events leading up to it. While Bree tries to save her marriage, Lynette struggles to find time and energy to cope with her children, Susan fights with Edie Britt for new neighbor Mike Delfino's affection, and Gabrielle tries to prevent her husband Carlos from discovering her affair with their underage gardener.

The second season began airing on September 25, 2005 and its central mystery is that of new neighbor Betty Applewhite, who moved in in the middle of the night. Throughout the season, Bree tries to cope with being a widow, unknowingly begins dating the man who poisoned her husband, fights alcoholism, and is unable to prevent the gap between her and her son to keep growing to extremes. Susan's love life gets even more complicated as her ex-husband gets engaged to Edie, who has been promoted to the role of fifth lead, Lynette goes back to her career in advertising and eventually becomes her husband's boss, and Gabrielle decides to be faithful to her husband, and begins preparations to have a child.

In season three, which began airing on September 24, 2006, Bree marries Orson Hodge, whose past and involvement with a recently discovered dead body becomes the main mystery for half of the season. Meanwhile, Lynette has to adjust to having another child around the house as a previously unknown daughter of her husband arrives, and the Scavos experience tension as Tom, Lynette's husband, wants to start a pizzeria. Gabrielle goes through a rough divorce, but finally finds new love in Fairview's new mayor. Edie sees her chance to make her move on Mike, who's suffering from amnesia, and Susan moves onto a handsome Englishman whose wife is in a coma. Edie's family relations are explored throughout the season.

The fourth season began airing on September 30, 2007, and its main mystery revolves around new neighbor Katherine Mayfair and her family, who returns to Wisteria Lane after twelve years away, whose daughter remembers nothing about living on Wisteria Lane. Also, Lynette battles cancer; the newlywed - but unhappy - Gabrielle starts an affair with her ex-husband Carlos; Susan and Mike enjoy life as a married couple and learn that they are expecting a child; Bree fakes a pregnancy and plans to raise her teenage daughter's illegitimate child as her own; and Edie schemes to hold on to her new love, Carlos. A gay couple from Chicago - Lee (Kevin Rahm) and Bob (Tuc Watkins) - become residents of Wisteria Lane when they move into the house formerly occupied by Betty Applewhite (Alfre Woodard), and Gloria and Alma Hodge.

The fifth season began airing on September 28, 2008, with the time period jumping five years ahead of the previous season, with some flashbacks to events which happened between the two periods. One of the first mysteries revolves around Edie Britt's new man, Dave Williams, played by Neal McDonough.