Second-generation antipsychotic drugs (eg, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone) have a reduced incidence of extrapyramidal side effects compared with first-generation neuroleptics, leading to increased use in psychiatric practice. However, some second-generation antipsychotic drugs can increase cardiometabolic risk by increasing risk for weight gain, dyslipidemia, and insulin resistance. Growing evidence, including baseline metabolic data from the CATIE study, indicates that patients with schizophrenia have an increased prevalence of metabolic syndrome (obesity, hypertension, hyperglycemia, dyslipidemia, and hyperglycemia). In CATIE Phase 1 and 2, treatment with different antipsychotic medications is associated with different effects on weight, plasma lipids and risk of hyperglycemia, ranging from clinically significant increases to decreases in metabolic risk. While mortality related to cardiovascular disease is elevated in this patient population, cardiovascular disease risk is under-monitored and under-treated. Current public health efforts aim to increase attention to this at-risk population. Long-term treatment strategies in persons with mental illness should aim to address psychiatric illness as well as key medical comorbidities.