Obesity prevalence has increased markedly over the past few decades. The obesity pandemic has huge implications for public health and our society. Although multiple studies show that the genetic contribution to obesity is significant, our genes have not changed appreciably over this time period. It was hypothesized that natural selection favors genotypes that result in a thrifty metabolism because individuals who carry these genotypes would be more likely to survive times of nutrient scarcity and to pass these genotypes to successive generations. Now that most of the world has adopted an increasingly "obesigenic" lifestyle of excess caloric intake and decreased physical activity, these same genes contribute to obesity and poor health. With the exception of the rare mutations that cause severe morbid obesity, it seems that numerous genes, each with modest effect, contribute to an individual's predisposition toward the more common forms of obesity. Variants in several candidate genes have been identified: association analyses and functional studies show that they contribute to modest obesity and related phenotypes. More recently, insights regarding gene-gene interactions have begun to emerge. Genome-wide scans for obesity phenotypes have led to the identification of several chromosome regions that are likely to harbor obesity susceptibility genes. Because of the increasing number of genome scans, several regions of replication have emerged. Positional cloning of these genes will undoubtedly unveil new insights into the molecular and pathophysiologic mechanisms of energy homeostasis and obesity.