Obesity is one of the most common physical health problems among patients with severe and persistent mental illnesses, such as schizophrenia. Multifactorial in origin, obesity can be attributed to an unhealthy lifestyle as well as the effects of psychotropic medications such as second-generation antipsychotics. Excess body weight increases the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, hypertension, and gallbladder disease. A PubMed search revealed 403 English-language citations to the query “schizophrenia” AND “obesity” and 469 citations to the query “obesity” AND “antipsychotics.” The evidence is that different antipsychotics have different propensities for weight gain, and that children, adolescents, and first-episode patients are at higher risk for weight gain associated with antipsychotic treatment. Monitoring body weight early in treatment will help predict those at high risk for substantial weight gain. Switching antipsychotic medication may or may not be clinically feasible, but can lead to a reduction in body weight. Lifestyle therapies and other nonpharmacological interventions have been shown to be effective in controlled clinical trials, but the evidence base for adjunctive medication strategies such as with orlistat, sibutramine, amantadine, nizatidine, metformin, topiramate, and others, is conflicting. At the very least, a “small-steps approach” to managing weight should be offered to all patients who are overweight or obese.