Obesity is one of the most pressing problems in the industrialized world. The susceptibility to obesity is partly determined by genetic factors, but an “obesity-promoting environment” is typically necessary for its phenotypic expression. Such a genetically mediated susceptibility to environmental exposure is referred to as gene-environment interaction. This article reviews the effect of genotype-diet interactions on body weight and body composition changes. A few well-controlled studies with monozygotic twins have specifically addressed the genetic background of interindividual variation in response to overfeeding or energy restriction. Some individuals will gain or lose weight more easily than others, but subjects sharing the same genotype (monozygotic twins) will respond in a similar way, suggesting that the responsiveness to diet is mediated by their genotype. Further evidence for gene-environment interactions comes from candidate gene studies. Genes involved in pathways regulating energy expenditure and food intake may play a role in the predisposition to obesity. For example, DNA sequence variation in genes encoding the adrenergic receptors and uncoupling proteins are of particular relevance. This growing body of research may help in the development of antiobesity treatments and perhaps genetic tests to predict the risk for obesity.