Today, the 'obesity pandemic' is one of the biggest health issues around the world. Melanin-concentrating hormone (MCH), a hypothalamic neuropeptide, is one of the most potent, central stimulators of feeding and it also attenuates energy expenditure. Inhibitions of the MCH receptor, the melanin-concentrating hormone receptor-1 (MCHR1), has attracted considerable attention as a potential anti-obesity drug, during the last decade. Now, there are a large number of MCHR1 antagonists, pharmacological tools and clinical drug candidates that can provide clues to develop new structures with high potency and good pharmacokinetic profile. The function of MCHR1 in energy homeostasis, obesity, metabolic syndrome, mood disorders and inflammatory bowel disease is discussed. Relevant clinical trials and patent background information of the MCHR1 antagonists over the last 4 years are also reviewed.