Psychotic symptoms frequently occur in patients with comorbid medical disorders and present a diagnostic and treatment challenge. They may be a part of an independent psychiatric illness associated with the underlying medical condition or induced by substance use or medications. The presence of psychotic symptoms can contribute to misdiagnosis or complicate the management of the comorbid medical illness. Psychiatrists must be familiar with the assessment and management of psychotic disorders in patients with comorbid medical disorders. Medications that may be used to treat psychosis include antipsychotic agents, benzodiazepines, or possibly certain anticonvulsants. Selecting the appropriate medication requires knowledge of the pharmacokinetics of different agents and their side effect profile. Understanding the neuropsychiatric effects of medications and drug-drug interactions may help in preventing psychotic symptoms.