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More than one-third of adults in the USA have obesity, which causes, exacerbates or adversely impacts numerous medical comorbidities, including diabetes mellitus and cardiovascular disease. Despite intensive lifestyle modifications, the disease severity warrants further aggressive intervention, including pharmacotherapy, medical devices and bariatric surgery. Noninvasive anti-obesity drugs have thus now resurfaced as targeted adjunctive therapeutic approaches to intensive lifestyle intervention, bridging the gap between lifestyle and bariatric surgery. In this Review, we discuss FDA-approved anti-obesity drugs in terms of safety and efficacy. As most of these drugs have a mean percentage weight loss reported in clinical trials but individual variations in response rates, a future direction of obesity pharmacotherapy research might include the potential for personalized medicine to target early responders to these anti-obesity drugs.