Family physicians commonly care for patients with serious mental illness. Patients with psychotic and bipolar disorders have more comorbid medical conditions and higher mortality rates than patients without serious mental illness. Many medications prescribed for serious mental illness have significant metabolic and cardiovascular adverse effects. Patients treated with second-generation antipsychotics should receive preventive counseling and treatment for obesity, hyperglycemia, diabetes, and hyperlipidemia. First- and second-generation antipsychotics have been associated with QT prolongation. Many common medications can interact with antipsychotics, increasing the risk of cardiac arrhythmias and sudden death. Drug interactions can also lead to increased adverse effects, increased or decreased drug levels, toxicity, or treatment failure. Physicians should carefully consider the risks and benefits of second-generation antipsychotic medications, and patient care should be coordinated between primary care physicians and mental health professionals to prevent serious adverse effects.