College professor Paul Rivers (Sean Penn) and his wife Mary (Charlotte Gainsbourg) find their union precariously balanced between life and death. He is mortally ill and awaiting a heart transplant, while she hopes to become pregnant with his child through artificial insemination. Cristina Peck (Naomi Watts), having matured since her reckless past, is a beloved older sister to Claudia (Clea DuVall), a good wife to Michael (Danny Huston) and loving mother to two little girls. Her family radiates hope and joy. Much farther down the socioeconomic scale, ex-con Jack Jordan (Benicio Del Toro) and his wife Marianne (Melissa Leo) struggle to provide for their two children while Jack reaffirms his commitment to religion.

A tragic accident that claims several lives places these couples in each other's orbit. In the aftermath, Paul confronts his own mortality, Cristina takes action to come to terms with her present and perhaps her future, and Jack's faith is put to the test. If spiritual equilibrium is to be regained by any one of them, it could come at great cost to the others. Yet the will to live, and the instinct to reach out to another person for support, remains ever-present among them all.

21 Grams, written by Guillermo Arriaga (Amores perros), explores the emotionally and physically charged existences of three people over a period of several months. An accident unexpectedly throws their lives and destinies together, in a story that will take them to the heights of love, the depths of revenge, and the promise of redemption.