The extent and consequences of medical comorbidity in patients with schizophrenia are generally underrecognized. Patients with comorbid conditions are usually excluded from research studies, although they probably represent the majority of individuals with schizophrenia. Elderly patients are especially likely to have comorbid disorders. In this article, we review selected literature on medical comorbidity in schizophrenia, including physical illnesses, substance use, cognitive impairment, sensory deficits, and iatrogenic comorbidity. Data from the University of California, San Diego Clinical Research Center on late-life psychosis are also presented. Older schizophrenia patients report fewer comorbid physical illnesses than healthy comparison subjects, but their illnesses tend to be more severe. These results suggest that schizophrenia patients may receive less than adequate health care. Substance abuse is more common in patients with schizophrenia than in the general population and may exacerbate psychiatric symptoms in these patients. Although generalized cognitive impairment is associated with schizophrenia, the main contributors to dementia in older patients are more likely to be comorbid neurological and other physical disorders, substance abuse, and medication side effects. Iatrogenic comorbidity results primarily from the use of neuroleptic (e.g., tardive dyskinesia) and anticholinergic (e.g., confusion) medications. Clinical and research recommendations are made for management of comorbidity in schizophrenia.