After a hit-and-run accident left Samantha Newly (Christina Applegate) in an eight-day coma, she awoke with retrograde amnesia, which allowed her to fully function in the world but leaves her with no personal memories of her past. As she began her quest to rediscover herself, she learned that she had been a horrible person. Vain, selfish and potentially surrounded by far more enemies than friends, she made a conscious decision to improve herself moving forward with the help of her eclectic friends and family.

In an attempt to reboot her life, Sam quits her job in order to find something that is more suitable to her "new" self, and moves out of her parents' home and back into her apartment -- where ex-boyfriend Todd (Barry Watson) has been living, rent free. She also feels it's time to move on from Todd and begin dating other men. But their feelings for each other are still strong, which could ultimately torpedo any possible romantic relationships they may find with other people. Sam's mother, Regina (Jean Smart, Emmy award winner for supporting actress in the show), afraid that she'll lose touch with her daughter again when she moves, entices her to partner in a mother/daughter real estate team. But father Howard (Kevin Dunn) will still have to act as mediator when the mother/daughter dynamics go awry. Changes are also in store for Sam's best friends Dena (Melissa McCarthy) and Andrea (Jennifer Esposito). Dena continues to date Sam's ex-boss -- and Andrea's current boss -- Mr. Chapman, but she so admires Sam's do-over in life that she will decide to make some changes of her own. As for the self-centered Andrea, she will begin dating a professional athlete -- a popular player at the top of his game and always in the spotlight. Andrea will, for the first time in her life, have to contend with the fact that she's not the center of attention in the relationship and may actually be dating out of her league. As for Frank (Tim Russ), the doorman at Sam's apartment, he will continue to be her reluctant spiritual advisor and confidant.

Sam will continue to try and make better choices in life, even though her instincts may not always steer her in the right direction. She will piece together things from her past to guide her in discovering who she is...or was. After all, sometimes to get to the end of the story, the only place to start is the beginning.