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 go to 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 of Huma Rojo (Marisa Paredes), who played Blanche. Emotionally devastated, Manuela relocates to Barcelona in hope of finding her ex-husband (and Esteban’s father), who is now working as a female impersonator.
Manuela becomes reacquainted with an old friend La Agrado (Antonia San Juan), a transsexual, 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).
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.