Approximately half of patients with schizophrenia have at least one comorbid psychiatric or medical condition, worsening prognosis and contributing to the high rate of morbidity and mortality. Depression is associated with suicide, the leading cause of premature death in patients with schizophrenia; obsessive-compulsive symptoms may worsen prognosis; alcohol and substance use disorders are associated with a poor outcome; and comorbid medical conditions, including cardiac and pulmonary disease, infectious diseases, diabetes, hyperlipidemia, hypogonadism, and osteoporosis, are often underrecognized and undertreated. The new generation of antipsychotic medications has improved the potential outcome of patients with schizophrenia. Providing optimal treatment for patients and fully realizing the potential of these new agents require focused attention on detection, recognition, and treatment of comorbid psychiatric and medical conditions in patients with schizophrenia.