This review examines weight loss and accompanying improvements in obesity-related comorbidities produced by intensive lifestyle intervention, pharmacotherapy, and bariatric surgery. Obese individuals lose approximately 6 to 8 kg (approximately 6% to 8% of initial weight) with 6 months of participation in a high-intensity lifestyle intervention (≥ 14 treatment visits) consisting of diet, physical activity, and behavior therapy. Such losses reduce progression to type 2 diabetes in at-risk people and decrease blood pressure and triglyceride levels. All diets, regardless of macronutrient composition, can produce clinically meaningful weight loss (> 5%) if they induce a deficit ≥ 500 kcal/d. Physical activity of 150 to 180 min/wk yields modest short-term weight loss compared with diet but contributes to improvements in obesity-related conditions. Gradual weight regain is common after lifestyle intervention but can be prevented by continued participation in monthly weight loss maintenance sessions, as well as by high levels of physical activity (ie, 200 to 300 min/wk). Patients unable to reduce satisfactorily with lifestyle intervention may be candidates for pharmacotherapy, recommended as an adjunct. Five medications have been approved by the US Food and Drug Administration for chronic weight management, and each has its own risk/benefit profile. The addition of these medications to lifestyle intervention increases mean weight loss by 2.5 to 8.9 kg compared with placebo. Patients with severe obesity who are unable to reduce successfully with lifestyle intervention and pharmacotherapy are eligible for bariatric surgery, including Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding. The first two procedures yield long-term (≥ 3 years) reductions of ≥ 20% of initial weight that are associated with decreases in morbidity and potentially mortality. Greater resources and dissemination efforts are needed to increase the availability of these three approaches for the millions of Americans who would benefit from them.