There is compelling genetic and pharmacologic evidence to indicate that melanin-concentrating hormone receptor-1 (MCHR1) signaling is involved in the regulation of food intake and energy expenditure. The medical need for novel therapies to treat obesity and related metabolic disorders has led to a great deal of interest by pharmaceutical companies in the discovery of MCHR1 antagonists. Recent publications describing preclinical studies have demonstrated that small-molecule MCHR1 antagonists decrease food intake, bodyweight, and adiposity in rodent models of obesity. Results from ongoing early-stage clinical trials with MCHR1 antagonists are eagerly awaited, as is the movement of other MCHR1 antagonists into the clinic.