The global increase in the prevalence of childhood obesity is attributed to recent changes in the environment (easy access to high-energy palatable food, combined with decreased physical activity). However, individual differences in obesity risk are mainly attributed to genetic variations. Being a complex heritable disorder, obesity results from the interplay between genetic susceptibility and the environment. Investigations exploring the genetic basis of obesity have identified numerous genes associated with syndromic, monogenic, oligogenic, and polygenic obesity. In this chapter, we comprehensively review 12 monogenic/oligogenic childhood obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin and directly related molecular pathways. Furthermore, we provide a clinical genetic testing strategy in order to improve the management of children with early-onset severe forms of obesity and discuss the development of new drugs that bypass the leptin signal.