A major factor in the context of evaluating depression in the elderly is the role of medical problems. With aging there is a rapid increase in the prevalence of a number of medical disorders, including cancer, heart disease, Parkinson’s disease, Alzheimer’s disease, stroke, and arthritis. In this article, we hope to bring clarity to the definition of comorbidity and then discuss a number of medical disorders as they relate to depression. We evaluate medical comorbidity as a risk factor for depression as well as the converse, that is, depression as a risk factor for medical illness. Most of the disorders that we focus on occur in the elderly, with the exception of HIV infection. This review focuses exclusively on unipolar disorder. The review summarizes the current state of the art and also makes recommendations for future directions.