What I Like About You tells the story of Valerie Tyler and her younger sister Holly. Valerie (Jennie Garth) is an uptight taskmaster who is very organized and somewhat neurotic. Her younger sister Holly (Amanda Bynes) is a rambunctious and narcissistic teenager who doesn't want to move to Tokyo where her father has a new job and instead arranges to move into her older sister's apartment with Val looking after her, this happening soon after Val's previous roommate Roberta (a character mentioned but not seen), who is mentioned as being a drama student who was of a very dark nature, moves out of the apartment. The show featured two strong sisters who love each other. They have equally loyal friends (Val's Lauren and Holly's Gary, for example).

Some of the early episodes featured physical comedy done by Amanda Bynes, which some critics complimented commenting Bynes' physical comedy was Lucille Ball-esque. However, the physical comedy was deemphasized in later episodes. The humor of the show spoofs on pop culture and uses extreme deadpan manner.

A key theme of the series is the Tyler sisters' exploits in love. Valerie's boyfriend Jeff (seen in the first season was one of four loves of hers). She was briefly attracted to two of her bosses Vic (Dan Cortese) and later Peter (Stephen Dunham). She was later engaged to an old flame Rick and later got married to Vic after a drunken night in Atlantic City. Holly's first love was Henry (Michael McMillian) and later dated Ben (David de Lautour) before hooking up with her true love Vince (Nick Zano).

The series frequently made references to previous episodes of the series starting with the second season giving the show continuity. Some of the show's storylines ran concurrently, and sometimes led into further developments, similar to that of the popular series Friends (a series co-creator Wil Calhoun previously wrote for).