Genetic influences on the determination of human fat mass are profound and powerful, a statement that does not conflict with the obvious influence of environmental factors that drive recent changes in the prevalence of obesity. The assertion of the importance of genetic factors has, until recently, largely been based on twin and adoption studies. However, in the last 6 yr, a number of human genes have been identified in which major missense or nonsense mutations are sufficient in themselves to result in severe early-onset obesity, usually associated with disruption of normal appetite control mechanisms. Progress in the identification of more common, subtler genetic variants that influence fat mass in larger numbers of people has been slower, but discernible. Human genetics will continue to make an invaluable contribution to the study of human obesity by identifying critical molecular components of the human energy balance regulatory systems, pointing the way toward more targeted and effective therapies and assisting the prediction of individual responses to environmental manipulations.