Whilst the recent rise in the prevalence of obesity has been driven in part by environmental factors, there is considerable evidence from twin and adoption studies that body weight and fat mass are highly heritable traits and differences in susceptibility to obesity have strong genetic determinants. The identification of patients with mutations in the gene encoding the adipocyte-derived hormone leptin, and their successful treatment with recombinant human leptin, have provided insights into the role of leptin responsive pathways in the regulation of eating behaviour, intermediary metabolism, the onset of puberty and T-cell mediated immunity. Leptin acts by regulating a complex network of brain responses that can be studied using functional imaging, to co-ordinate changes in nutritional state with changes in food intake and the liking of food. A downstream target of leptin action, the melanocortin 4 receptor (MC4R), plays a key role in modulating sympathetic nervous system mediated changes in blood pressure. Recently, genome wide approaches are proving to be an increasingly important tool in understanding the genetic heterogeneity associated with common obesity. The recognition that copy number variants contribute to a significant proportion of genetic variation at an individual and at a population level opens up new routes to gene discovery which will drive further understanding of the molecular pathways involved in energy homeostasis.