The compelling genetic and pharmacological evidence implicating melanin-concentrating hormone-1 receptor (MCH-1R) signalling in the regulation of food intake and energy expenditure has generated a great deal of interest by pharmaceutical companies for the discovery of MCH-1R antagonists, evidenced by the increased number of patents describing MCH-1R antagonists for the treatment of obesity and metabolic syndrome. The structural diversity of small molecular weight drug-like MCH-1R antagonists produced and preclinical studies showing hypophagia and weight loss with small molecular weight and peptidal antagonists in rodents is encouraging and suggests that the identification of clinical candidates will be forthcoming.