Obesity is a serious and growing worldwide health challenge. Healthy lifestyle choices are the foundation of obesity treatment. However, weight loss can lead to physiological adaptations that promote weight regain. As a result, lifestyle treatment alone typically produces only modest weight loss that is difficult to sustain. In other metabolic diseases, pharmacotherapy is an accepted adjunct to lifestyle. Several anti-obesity drugs have been approved in the USA, European Union, Australia, and Japan including sympathomimetics, pancreatic lipase inhibitors, GABA receptor activators, a serotonin 2C receptor agonist, opioid antagonist, dopamine-norepinephrine reuptake inhibitor, and glucagon-like peptide-1 (GLP-1) receptor agonists. These drugs vary in their efficacy and side-effect profiles but all provide greater weight loss than do lifestyle changes alone. Even though obesity is widespread and associated with adverse health consequences, and anti-obesity drugs can help people to lose weight, very few patients use these drugs partly because of concerns about safety and efficacy, but also because of inadequate health insurance coverage. Despite great advances in our understanding of the biology of weight regulation, many clinicians still believe that patients with obesity should have the willpower to eat less. The tendency to hold the patient with obesity responsible for their condition can be a barrier to greater acceptance of anti-obesity drugs as appropriate options for treatment. Physicians should be comfortable discussing the risks and benefits of these drugs, and health insurance companies should provide reasonable coverage for their use in patients who are most likely to benefit. Although few promising anti-obesity medications are in the drug-development pipeline, the most promising drugs are novel molecules that are co-agonists for multiple gut hormones including GLP-1, glucagon, and gastric inhibitory peptide.