A considerable amount of research on the genetics of obesity has been reported in the past few years. Despite evidence that genetic factors play a significant role in the etiology of this nutritional disease and the increasing number of obesity genes identified, relatively little is known about the role of genes in the response of obesity phenotypes to alterations in energy balance or diet composition. This is especially true for dietary fat, which is known to be associated with obesity at the population level. The aim of this review was to summarize the evidence currently available about the role of gene-nutrient interactions in human obesity. Evidence from both genetic epidemiology and molecular epidemiology studies suggests that genetic factors are involved in determining the susceptibility to gaining or losing fat in response to diet or the risk of developing some of the comorbidities generally observed in obese individuals. Recent evidence suggests that quantitative trait loci identified from animal models of diet-induced obesity could influence body fat in humans. Despite the limited number of studies, the evidence on gene-diet interactions in obesity is convincing. More research is needed to identify the genes responsible for these interaction effects, and the use of animal models of diet-induced obesity represents a promising approach. Finally, data on children are needed to allow assessment of the tracking of nutrient intake between childhood and adulthood. In addition, gene-diet interactions in children need to be investigated to determine whether the genes involved are the same as those found in adults.