Underlying medical illness may present a challenge when prescribing psychotropic medications. Disease-related changes in pharmacokinetics and pharmacodynamics, as well as vulnerability to side effects, polypharmacy, and potential drug interactions are all important considerations. Successful treatment of psychiatric disorders may have a beneficial impact on medical morbidity and mortality, as well as quality of life. This article reviews the relevant considerations when using psychotropic medications in six major medical populations (cardiac, cerebral vascular, pulmonary, liver, renal, and seizure disorders).