Pharmacological therapy for obesity is in transition. Historically,there have been few effective agents, and many have been with-drawn because of unacceptable side effects. Current options include three medications approved by the FDA for the treatment of obesity: phentermine, sibutramine and orlistat. Phentermine and sibutramine suppress appetite and promote thermogenesis,and orlistat blocks fat digestion and absorption in the gut. Several drugs approved for other indications often promote weight loss, including bupropion, metformin, topiramate and zonisamide; they have been used empirically for treatment of obesity and to counter the weight-promoting effects of other medications. Expanding knowledge of the physiological mechanisms of body weight regulation has revealed new molecular targets, and more than 150 novel agents are under active development. Because weight regulation is complex, and redundant systems protect against perceived starvation, optimal treatment of obesity will likely require combinations of therapies. The accelerating emergence of new medications will facilitate the development of such effective combinations.