A man is picked up by a fishing boat, bullet-riddled and suffering from amnesia, before racing to elude assassins and attempting to regain his memory.

Based on Patrick DeWitt's novel, The Sisters Brothers revolves around the colorfully named gold prospector Hermann Kermit Warm, who's being pursued across 1000 miles of 1850s Oregon desert to San Francisco by the notorious assassins Eli and Charlie Sisters. Except Eli is having a personal crisis and beginning to doubt the longevity of his chosen career. And Hermann might have a better offer.