Obesity is an increasingly prevalent and important health problem. Although treatment is available, the long-term maintenance of medically significant weight loss (5 to 10 percent of initial body weight) is rare. Since 1995 there has been an explosion of research focused on the regulation of energy balance and fat mass. Characterization of obesity-associated gene products has revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Ideally, these treatments will be viewed as adjuncts to behavioral and lifestyle changes aimed at maintenance of weight loss and improved health.