Melanin-concentrating hormone (MCH) is a neuropeptide that was originally isolated from salmon pituitary where it causes pigment aggregation. MCH is also abundantly present in mammalian neurons and expressed in the lateral hypothalamus and zona incerta, brain regions that are known to be at the center of feeding behavior. MCH binds to and activates two G protein-coupled receptors, MCH1R and MCH2R. Although MCH2R is non-functional in rodents, genetic and pharmacological studies have demonstrated that rodent MCH1R is involved in the regulation of feeding behavior and energy balance. Unexpectedly, some antagonists have provided evidence that MCH signaling participates in the regulation of other processes, such as emotion and stress. The discovery of MCH receptors has extensively promoted the progress of MCH studies and may represent an ideal example of how deorphanized receptors can open new directions toward more detailed physiological studies.