Manuela (Cecilia Roth) is a single mother who has raised her son Esteban (Eloy Azorin) to adulthood on her own and has come to emotionally depend on him. One night, Manuela and Esteban take in a production of A Streetcar Named Desire; after the show, Esteban is struck and killed by a passing motorist as he dashes into the street to get an autograph from Huma Rojo (Marisa Paredes), who played Blanche.
Emotionally devastated, Manuela relocates to Barcelona in hopes of finding her ex-husband (and Esteban’s father), who is now working as a female impersonator. Manuela becomes reacquainted with old friend La Agrado (Antonia San Juan), a transexual, and is introduced to Sister Rosa (Penelope Cruz), a good-hearted nun who has to contend with her considerably more cynical mother (Rosa Maria Sarda). While looking for work, Manuela becomes acquainted with Huma Rojo. Huma, on the other hand, has troubles of her own, most involving her drug-addicted significant other, Nina (Candela Pena).
Todo sobre mi madre cuenta la historia de Manuela, que tendrá que enfrentarse al pasado y a los recuerdos tras la muerte de su hijo. Este suceso marcará su vida y la hará volver a Barcelona en busca del padre del adolescente que desconocía la existencia de éste. En su búsqueda, se irá encontrando a personajes que en tiempos anteriores la habían ayudado y que ahora le darán nuevas razones para seguir viviendo.
