Obesity is a global health crisis resulting in major morbidity and premature death. The need for safe and efficacious drug therapies is great, and presently unmet. The two drugs currently licensed in the USA for the long-term treatment of obesity, orlistat and sibutramine, provide only modest weight-loss benefits and are associated with high attrition rates owing to side effects. This review summarizes current concepts in the neuroendocrine control of energy homeostasis and major pharmacological treatments for obesity in the pipeline.