An overfeeding experiment conducted with 12 pairs of young male identical twins revealed that genetic factors were likely to play an important role in the response to caloric affluence. Significant intrapair resemblance was observed for the overfeeding-induced changes in body weight, fat mass, abdominal fat, fasting insulin, fasting cholesterol and triglycerides. In an attempt to define the molecular basis of these genotype–energy balance interaction effects, a panel of candidate genes has been investigated. Among the most significant findings, an adipsin polymorphism was associated with increases in body weight, total fat mass and subcutaneous fat in response to overfeeding. In addition, the beta2 adrenergic receptor gene Gln27Glu polymorphism showed a strong association with the gains in body weight and subcutaneous fat. Only a few markers were related to abdominal fat changes and, among them, the adipsin Hinc II polymorphism was associated with both computed tomography (CT)-measured abdominal visceral and total fat. The changes in insulin parameters brought about by long-term overfeeding were influenced most consistently by leptin receptor (LEPR) Gln223Arg and insulin-like growth factor-II Apa I polymorphisms. The LEPR Gln223Arg variant was also associated with the changes in plasma total triglycerides and high-density lipoprotein cholesterol concentrations. Further research with larger sample sizes should make it possible to identify the specific contributions of DNA sequence variations at multiple candidate gene loci in the complex response to chronic positive energy balance.