The Sisters Brothers is a novel about Eli and Charlie Sisters, two small-time criminals who are hired by a rich businessman to kill a California gold prospector during the Gold Rush. Generically, the book has been described as Western noir, a black comedy, and a picaresque novel. It is narrated by Eli, a more sympathetic and reflective character than his brother, Charlie.
The book addresses various themes. One is the value of human life and the morality of killing, a subject which troubles Eli. Paradoxically, it is by committing a murder (though not the one he was hired to commit) that Eli manages to escape from his career as an assassin. Another theme is masculinity. Throughout the novel, Charlie is the more conventionally masculine of the two brothers, the epitome of the strong, silent "tough guy." However, he is emasculated and the roles of the two brothers are reversed when the hand with which he shoots is severely burned and has to be amputated.
Finally, the book explores the corrupting effects of greed and capitalism. The man the brothers are tasked with killing has concocted a formula for finding gold, but the mixture is highly caustic. It is this that burns Charlie's hand. This formula serves as a powerful metaphor for the harm caused by the relentless pursuit of gold.