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Individuals with serious mental illness experience excess morbidity and mortality, including an increased prevalence of diabetes mellitus and cardiovascular disease. Cardiovascular disease is the leading cause of death in persons with serious mental illness, and the elevated prevalence of obesity in this population is of particular concern. Obesity is an independent cardiometabolic risk factor that impacts morbidity and mortality and contributes to the development of other cardiometabolic risk factors, such as dyslipidemia and hypertension. In addition, obesity is a major risk factor for type 2 diabetes, with the relative risk of diabetes increasing with body mass index. Increased abdominal fat is strongly associated with insulin resistance, which can lead to impaired glucose regulation. Abdominal obesity, hyperglycemia, hypertension, and dyslipidemia are key components of the metabolic syndrome, a constellation of cardiometabolic risk factors linked by their common association with insulin resistance. Evidence from large clinical samples indicates a high prevalence of metabolic syndrome and all of its components in persons with serious mental illness, particularly in patients with schizophrenia. In addition, psychotropic agents, including some antipsychotic medications, are associated with substantial weight gain, as well as with adiposity-dependent and possibly adiposity-independent changes in insulin sensitivity and lipid metabolism, which increase the risk of diabetes and cardiovascular disease. Among the second-generation antipsychotics, clozapine and olanzapine are associated with the highest risk of substantial weight gain, similar to the weight gain potential associated with low-potency first-generation antipsychotics such as thioridazine or chlorpromazine, as well as with an increased risk of diabetes and dyslipidemia. Various strategies for monitoring cardiometabolic risk factors in patients with mental illness are discussed in this review.