Obesity is one of the most challenging health problems worldwide. Over the past few decades, our knowledge concerning mechanisms of weight regulation has increased tremendously leading to the identification of the leptin-melanocortin pathway. The filling level of energy stores is signaled to the brain, and the information is integrated by hypothalamic nuclei, resulting in a well-orchestrated response to food intake and energy expenditure to ensure constant body weight. One of the key players in this system is proopiomelanocortin (POMC), a precursor of a variety of neuropeptides. POMC-derived alpha- and beta-MSH play an important role in energy homeostasis by activating melanocortin receptors expressed in the arcuate nucleus (MC3R) and in the nucleus paraventricularis (MC4R). Activation of these two G protein-coupled receptors is antagonized by agouti-related peptide (AgRP). Naturally occurring mutations in this system were identified in patients suffering from common obesity as well as in patients demonstrating a phenotype of severe early-onset obesity, adrenal insufficiency, red hair, and pale skin. Detailed understanding of the complex system of POMC-AgRP-MC3R-MC4R and their interaction with other hypothalamic as well as peripheral signals is a prerequisite to combat the obesity epidemic.