It is said that much of the world is experiencing an “epidemic of obesity.” This statement is based on statistics showing that in the USA and many other countries, 30–40% of the population is above optimal weight, and that the excess weight (especially abdominal fat) is often associated with the metabolic syndrome and increased risks of cardiovascular disease and diabetes. Since eating behavior is an expression of endocrine, neurophysiologic, and psychological processes, prevention and treatment of obe-sity are challenging. There is considerable scientific and financial interest in developing pharmacologic therapy for the condition. Although obesity can be defined as excess adipose tissue, it is currently quantitated by means of the body mass index (BMI), calculated from BMI = weight (in kilograms)/height2 (in meters). Using this measure, the range of normal BMI is defined as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly obese (ie, at very high risk), ≥40. (Underweight persons, ie, those with a BMI < 18, also have an increased [but smaller] risk of health problems.) Some extremely muscular individuals may have a BMI higher than 25 and no excess fat; however, the BMI scale gener-ally correlates with the degree of obesity and with risk. A second metric, which may be an even better predictor of cardiovascular risk, is the ratio of waist measurement to body height; cardiovas-cular risk is lower if this ratio is less than 0.5. Experts consider drug therapy to be justified in patients with increased risk factors and a BMI ≥ 27 and in those without comorbidities but with a BMI ≥ 30. Although the cause of obesity can be simply stated as energy intake (dietary calories) that exceeds energy output (resting metabolism plus exercise), the actual physiology of weight con-trol is extremely complex, and the pathophysiology of obesity is still poorly understood. Many hormones and neuronal mecha-nisms regulate intake (appetite, satiety), processing (absorption, conversion to fat, glycogen, etc), and output (thermogenesis, muscle work). The fact that a large number of hormones reduce appetite might appear to offer many targets for weight-reducing drug therapy, but despite intensive research, no available phar-macologic therapy has succeeded in maintaining a weight loss of over 10% for 1 year. Furthermore, the social and psychological aspects of eating are powerful influences that are independent of or only partially dependent on the physiologic control mecha-nisms. In contrast, bariatric (weight-reducing) surgery readily achieves a sustained weight loss of 10–40%. Furthermore, surgery that bypasses the stomach and upper small intestine (but not simple restrictive banding) rapidly reverses some aspects of the metabolic syndrome even before significant loss of weight. Even a 5–10% loss of weight is associated with a reduction in blood pres-sure and improved glycemic control. Gastrointestinal flora also influence metabolic efficiency, and research in mice suggests that altering the microbiome can lead to weight gain or loss. Until approximately 15 years ago, the most popular and successful appetite suppressants were the nonselective 5-HT2 agonists fenfluramine and dexfenfluramine. Combined with phentermine as Fen-Phen and Dex-Phen, they were moderately effective. However, these 5-HT2 agonists were found to cause pulmo-nary hypertension and cardiac valve defects and were withdrawn. Older drugs still available in the USA and some other countries include phenylpropanolamine, benzphetamine, amphetamine, methamphetamine, phentermine, diethylpropion, mazindol, and phendimetrazine. These drugs are all amphetamine mimics and are central nervous system appetite suppressants; they are generally helpful only during the first few weeks of therapy. Their toxicity is significant and includes hypertension (with a risk of cerebral hemorrhage) and addiction liability. Liraglutide, lorcaserin, orlistat, and phentermine are the only single-agent drugs currently approved in the USA for the treat-ment of obesity. In addition, combination agents (phentermine plus topiramate and naltrexone plus bupropion) are available. These drugs have been intensely studied, and some of their prop-erties are listed in Table 16–5. Clinical trials and phase 4 reports suggest that these agents are modestly effective for the duration of therapy (up to 1 year) and are probably safer than the single-agent amphetamine mimics. However, they do not produce more than a 5–10% loss of weight. Mirabegron, a β3 adrenoceptor agonist approved for the treatment for overactive bladder (see Chapter 9), is of possible future interest because β3 agonists activate brown fat to consume more energy. Sibutramine and rimonabant were marketed for several years but were withdrawn because of increas-ing evidence of cardiovascular and other toxicities. Because of the low efficacy and the toxicity of the available drugs, intensive research continues. Because of the redundancy of the physiologic mechanisms for control of body weight, it seems likely that polypharmacy targeting multiple pathways will be needed to achieve success.