Obesity represents one of the biggest public health challenges facing us today. Urbanisation, sedentary lifestyles and the availability of inexpensive, highly palatable foods have promoted the increasing prevalence of obesity over the past 30 years. However, some people gain weight more easily than others, and there is strong evidence that, within a given environment, this variance in body weight is influenced by genetic factors. This article discusses how genetic studies have contributed to our understanding of the mechanisms involved in the regulation of body weight. We now understand that weight is regulated by neural mechanisms that regulate appetite and energy expenditure and that disruption of these pathways can result in severe obesity in some patients. These studies provide a framework for investigating patients and ultimately may guide the development of more rational, targeted therapies for genetically susceptible individuals with severe obesity.