To curb the epidemic of obesity in the United States, revised Medicare policy allows support for efficacious obesity treatments. This review summarizes the evidence from rigorous randomized trials (9 lifestyle trials, 5 drug trials, and 2 surgical trials) on the efficacy and risk-benefit profile of lifestyle, drug, and surgical interventions aimed at promoting sustained (= 2 years) reductions in weight. Both lifestyle and drug interventions consistently produced an approximate 7-lb (3.2-kg) weight loss that was sustained for 2 years and was associated with improvements in diabetes, blood pressure, and/or cardiovascular risk factors. Surgical interventions have a less solid empirical base but offer promise for the promotion of significant and sustained weight reduction posttreatment in the morbidly obese but with possible significant short-term side effects. In summary, there is strong and consistent support from rigorous randomized trials that lifestyle or drug interventions result in modest weight loss with minimal risks but disproportionate clinical benefit. Combinations of lifestyle, drug, and, where appropriate, surgical interventions may be the most efficacious approach to achieving sustained weight loss for the widest diversity of patients.