Obesity is a disorder characterized by an excess accumulation of body fat resulting from a mismatch between energy intake and expenditure. Incidence of obesity has increased dramatically in the past few years, almost certainly fuelled by a shift in dietary habits owing to the widespread availability of low-cost, hypercaloric foods. However, clear differences exist in obesity susceptibility among individuals exposed to the same obesogenic environment, implicating genetic risk factors. Numerous genes have been shown to be involved in the development of monofactorial forms of obesity. In genome-wide association studies, a large number of common variants have been associated with adiposity levels, each accounting for only a small proportion of the predicted heritability. Although the small effect sizes of obesity variants identified in genome-wide association studies currently preclude their utility in clinical settings, screening for a number of monogenic obesity variants is now possible. Such regular screening will provide more informed prognoses and help in the identification of at-risk individuals who could benefit from early intervention, in evaluation of the outcomes of current obesity treatments, and in personalization of the clinical management of obesity. This Review summarizes current advances in obesity genetics and discusses the future of research in this field and the potential relevance to personalized obesity therapy.