Over recent decades, the prevalence of obesity has increased dramatically worldwide. Although this epidemic is mainly attributable to modern (western) lifestyle, multiple twin and adoption studies indicate the significant role of genes in the individual's predisposition to becoming obese. As the hypothalamus plays a central role in controlling body weight, its regulatory circuits may represent a crucial system in the pathogenesis of the disorder. Genetic variations in genes in the hypothalamic pathways may therefore contribute to the susceptibility for obesity in humans and animals. We summarize current knowledge on the physiological role of the hypothalamus in body-weight regulation and review genetic studies on the hypothalamic candidate genes in relation to obesity. Together, data from functional and genetic studies as well as the new, common, obesity loci identified in genome-wide association scans support an important role for the hypothalamic genes in predisposing to obesity. However, findings are still inconclusive for many candidate genes. To improve our understanding of the genetic architecture of common obesity, we suggest that specific obesity phenotypes should be considered and different analytical approaches used. Such studies should consider multiple genes from the same physiological pathways, together with environmental risk factors.