The novel begins with a phone call from Caitlin to Vix. Caitlin calls to tell Vix that she is marrying Vix's ex-boyfriend and first love, Bru. Vix is shocked and becomes sick with the news.
Flashback: Now the reader learns of Vix's family and first encounter with Caitlin. Vix's home life consists of her controlling mother, Tawny, an average-joe father, and three younger siblings, Lanie, Lewis, and Vix's favorite: her wheelchair-using brother Nathan. Tawny works for a Countess and is always making Vix feel as though she is not good enough. Then Vix meets Caitlin in her sixth grade class, and Caitlin invites Vix to come to Martha's Vineyard with her for the summer. This is when Vix's whole world is turned upside down.
After much debate, Vix convinces Tawny and her father to let her go with Caitlin. Vix flies out East from her New Mexico ranch and meets Caitlin's family: her laid-back father, Lambert "Lamb" Somers, her brother "Sharkey", and Trisha, an ex-girlfriend of Lamb's who is still close with him but has recently been replaced by Abby, a woman who means well but whom Caitlin dislikes. Abby's son, Daniel, and his friend, Gus, also vacation with Caitlin's family. This section of the book focuses on the mishaps and adventures that the kids go through, including Vix and Caitlin and their crushes on two older boys, Joseph "Bru" Brudegher and his cousin, Von.
When the summer ends, Caitlin and Vix remain friends and continue to attend school together. They make it a tradition for Vix to spend every summer with Caitlin from then on, hence the "Summer Sisters." Eventually, Vix hooks up with Bru and Caitlin with Von. Then Vix makes out with Von while high. She thinks that Caitlin set up the whole scenario and they get into a huge argument. Just prior to her senior year of high school, Vix's beloved brother Nathan succumbs to his physical disabilities and dies as a result, leaving Vix devastated. Vix's younger sister, Lanie, becomes pregnant and has her first child, and Lewis joins the military. As the girls mature, they encounter their first heterosexual experiences (Caitlin with an Italian ski-instructor, then Von, supposedly) and Vix's in-depth and long-term relationship with Bru, which continues into her college years when she attends Harvard on a scholarship from The Somers Foundation. Caitlin is accepted to Wellesley College but chooses not to attend and travels abroad.
Vix goes to Harvard while still remaining in a relationship with Bru. She makes new friends, most notably Maia, her uptight roommate whose worrisome ways begin to grow on Vix, but they become close. However, things turn sour when Vix realizes she doesn't know what she wants in life and she and Bru temporarily break up during her Junior year of college. A few months later, a passionate meeting leads to their renewed faithfulness, but all's well does not end well. Just before graduation, Bru asks Vix to marry him, but she says no after realizing that they do not want the same things in life. Vix misses Bru, but moves on and casually dates other people, whilst Caitlin has numerous hetero and homosexual escapades in Europe. The girls keep in loose contact over the years, each becoming busy with her own life until the fateful day when Caitlin makes that phone call and tells Vix about her upcoming nuptials to Bru.
Caitlin invites Vix to the wedding, and she decides to go, only to end up sleeping with Bru the night before. Then, Vix discovers that Bru took not only her virginity but Caitlin's as well. As Bru thinks in the book, "he loves them both... he is glad they have decided for him [who he will be with.]" Caitlin and Bru get married nonetheless, and Caitlin has a daughter, Somers Mayhew Brudegher, whom they call "Maizie". Vix, meanwhile, reconnects with Abby's son Daniel's friend Gus, whom she spent all those summers with years ago at the vineyard. She and Gus slowly fall in love and eventually get married as well. In the final chapters, Vix visits Caitlin again after Caitlin has a breakdown and leaves her family, her marriage to Bru ending in divorce and Bru marrying Star, a local islander. Vix is pregnant with her first child at this time, a baby boy to be named Nate in honor of her late brother. Caitlin and Vix's meeting is relaxed and the two end up pledging to be best friends forever with each one truly grateful for the other's presence in her life.
In the end, Vix is enjoying married life and motherhood when she and everyone else learn that Caitlin disappears in an alleged boating accident... she was in a boat by herself and that was the last time anyone ever saw her, as the boat turned up empty with Caitlin unaccounted for. Blume is not clear on the true reasons behind Caitlin's disappearance, as no body is discovered and there is no damage or foul play, leading the reader to choose between the possibilities that Caitlin purposely vanished from her family and friends or perhaps she did indeed drown. The closing thought is Vix's recount of her "summer sister" and the memories they will always share, and wishing that things could have ended differently.