Obesity is one of the most important health problems today. Obesity is mostly caused by a complex interaction between environmental and genetic factors. However, several monogenic forms of obesity also exist. The mutations causing these forms of obesity were all found in genes involved in the leptin-melanocortin pathway: leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1, and melanocortin-4 receptor. Recently, several novel players with a role in this pathway have been identified and have increased our knowledge on the regulation of food intake. These include the melanocortin-3 receptor, BDNF, SIM1, and nesfatin-1. In this review, we will discuss the most important players involved in this pathway. We will focus on genetic studies concerning mouse models involving these genes and reported human variation in these genes. We intend to provide an extensive overview of all currently known proteins with a significant role in this pathway. Together, these data demonstrate the importance of this pathway in the regulation of food intake and the pathogenesis of obesity.