Technical Abstract: A vast body of research exists to demonstrate that obesity is a complex disorder with a strong genetic basis and a multifactorial etiology. Yet despite the overwhelming evidence that genes play an important role in the development of obesity, many people argue that the increasing prevalence of obesity is simply due to an abundance of palatable food and a dearth of opportunities for physical exercise. While activity and eating behaviors contribute substantially to the development of obesity, considering these to be the only etiologic factors is directly contradictory to what is now known about how eating and energy balance are regulated. Our understanding of the molecular processes controlling eating behavior, in particular, has accelerated exponentially in the last 10 years, and this is one area in which obesity genetics has made great progress. Our challenge is to understand more fully how genetic variation may interact with behavioral factors to influence the regulation of body weight and adiposity. Although exercise and diet strategies are used routinely for obesity treatment, there is a huge variability in how individuals respond to these interventions. There is also a substantial amount of evidence that such responses may also be regulated by genes. Understanding gene–response relationships is the key to developing more efficacious intervention and prevention programs for obesity.