During the past several decades, there has been an explosion in the prevalence of obesity. Since our genes have not changed appreciably during that time, it stands to reason that the present epidemic is caused by our pervasive obesigenic environment, in which excess caloric intake and decreased physical activity conspire with one another. Despite an obesigenic environment, humans have great variability in their susceptibility to obesity, which is determined in large part by genetics. Current evidence suggests that genetic susceptibility to human obesity is the result of multiple genes, each with a modest effect, that inter-act with each other and with environmental provocations. Elucidation of obesity susceptibility genes through genome-wide and candidate gene approaches provides great promise in ultimately determining the genetic underpinnings of obesity. Further research will translate these new insights on the pathophysiological basis of obesity into new medications and diagnostic tests.