It is an inescapable fact that the underlying cause of obesity is a result of consuming more energy than you burn. The question that is more complex to answer is why some people eat more than others. Over the past 15 years, insights from human and mouse genetics have illuminated multiple pathways within the hypothalamus, brainstem and higher brain regions that play a key role in the control of food intake. We now know for example, that the brain leptin-melanocortin signalling pathway is central to the control of mammalian food intake. Intriguingly, it is becoming clear that in addition to engaging classical “neuropeptide/receptor” systems within the brain, leptin also rapidly modifies synaptic connections between neurons. There is also evidence for neurotrophins, which are critical in the development and maintenance of neuronal connections, playing a role in the control of energy homeostasis. However, although monogenic alterations in these pathways result in extreme Mendelian obesity, these remain incredibly rare. The major burden of disease is carried by those of us with “common obesity,” which to date has resisted yielding meaningful biological insights. Progress however, has been made with genomewide association studies. For example, sequence variants in the first intron of FTO (Fat mass and Obesity related) are strongly associated with human obesity and carriers of the risk alleles show evidence for increased appetite and food intake. Although global FTO null mice display decreased fat and lean body mass, increased metabolic rate and food intake, this is seen against a complex phenotype of postnatal growth retardation and mortality. In contrast, when we modulated FTO levels discretely in the hypothalamic arcuate nuclei of adult animals, we were able to influence food intake, suggesting tissue specific functions for FTO. FTO’s physiological role and how it influences bodyweight is yet to be determined. Using a variety of in vivo, in vitro and biochemical methods, we are currently characterising the molecular mechanism by which FTO controls of energy balance. Further GWAS have now revealed more than 30 different candidate 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.