Oregon, 1851: They are notorious, the Sisters Brothers. Eli, the older, and Charlie, the younger (JOHN C. REILLY and JOAQUIN PHOENIX), one calm and deliberate, the other a belligerent drunk. Ruthless hit men in the service of an ominous "Commodore." Corpses pave their way. On their hands is blood, not only of criminals, but also of innocent people. For a large sum of money they are supposed to kill a certain Hermann Warm (RIZ AHMED), who has invented a miracle formula for easy gold panning: A liquid makes the gold nuggets visible in the water. A knowledge that can earn the "Commodore" a fortune. Also hot on the genius's heels is their contact Jim Morris (JAKE GYLLENHAAL). While the Brothers ride from the mountains of Oregon to California, leaving a murderous trail behind them, Morris is several days ahead of them and meets the wanted chemist in a trek. Instead of turning him over to the Sisters Brothers, he pursues goals all his own. When the four men collide, it's first a matter of life or death. But the gold beckons... With extraordinary actors like John C. Reilly, Joaquin Phoenix, Jake Gyllenhaal and Riz Ahmed, who outgrow themselves in their performances, and in beguiling images against a breathtaking landscape, filmed in Spain and Romania, he tells, based on a novel by Patrick de Witt, of the compulsions to violence in a male society, of the longing for middle-class life, of the utopia of a fairer world, of people as pawns of fate. In doing so, he takes a close look at America's founding myth and defies all genre conventions. A great Western, dark and melancholy, funny and ironic, and at the end with a glimmer of hope for humanity.