The data reviewed in this paper reveal that individual differences in the response to alterations in energy balance induced by diet or exercise are ubiquitous. These differences are observed in a variety of obesity-related phenotypes, including body weight, body fatness, and abdominal visceral fat. Although little is known about the causes of the heterogeneity in responsiveness to dietary habits or to regular exercise, the evidence accumulated so far suggests that genetic factors may play an important role in determining the response of body mass and body fat stores to chronic alterations in energy balance. It is likely that genetic variation at several genes contributes to this heterogeneity of responses and thus to the susceptibility to obesity. Research on the genetic and molecular basis of gene-environment interactions has become a major area of investigation. One can, therefore, anticipate that major advances will occur in the coming years with respect to the identification of the genetic and molecular causes of the susceptibility to the most common diseases, including obesity.