Over the past 20 years, genetic studies have illuminated critical pathways in the hypothalamus and brainstem mediating energy homeostasis, such as the melanocortin, leptin, 5-hydroxytryptamine and brain-derived neurotrophic factor signaling axes. The identification of these pathways necessary for appropriate appetitive responses to energy state has yielded insight into normal homeostatic processes. Although monogenic alterations in each of these axes result in severe obesity, such cases remain rare. The major burden of disease is carried by those with common obesity, which has so far resisted yielding meaningful biological insights. Recent progress into the etiology of common obesity has been made with genome-wide association studies. Such studies now reveal more than 32 different candidate obesity genes, most of which are highly expressed or known to act in the CNS, emphasizing, as in rare monogenic forms of obesity, the role of the brain in predisposition to obesity.