Comorbidity is a common issue in psychiatric practice. A particular subset of this issue are patients who have comorbid medical and psychiatric illness. For many of these patients, their medical disorders may affect the course of their psychiatric illness, and in some, the psychiatric illness may be implicated in the course and outcome of their medical illnesses. Regardless of the direction of the effect everyone who treats psychiatric illness in general medical or psychiatric settings needs to be aware of these bidirectional effects and their potential impact on diagnosis, effect of treatments, and in some cases mortality. This chapter reviews the data on comorbidity, the ways in which these conditions can interact, models of ameliorating the impact of comorbidity, and the role of general physicians and other healthcare clinicians in caring for comorbid psychiatric patients. Data on the impact of psychiatric illness on the total cost of medical care, models for working collaboratively between psychiatrists and primary care practitioners, and implications for training of physicians and other clinicians are reviewed.