Vitamin D is important for cell growth, immunity, and metabolism. Deficiency has classically been associated with rickets and decreased bone density and more recently with increased risk and severity of autoimmune diseases, cancers, myocardial infarction, diabetes, and infectious diseases. How vitamin D can affect these diverse conditions is the subject of much research. The active form of vitamin D (vitamin D3) has been implicated recently in an intracellular process known as autophagy. In addition to its role in maintaining cellular homeostasis during conditions of stress, autophagy plays an important role in the control of many intracellular microorganisms including Mycobacterium tuberculosis. Recent work has identified that HIV-1 reduces autophagy during permissive infection and that agents that induce autophagy, including vitamin D3, can inhibit HIV-1 replication. These findings help provide a biological explanation for the increased risk of more rapid disease progression observed in HIV-infected persons with low levels of vitamin D or with genetic variants within the vitamin D receptor that alter binding to vitamin D. Controlled trials are needed to determine the potential for therapeutic benefit of vitamin D supplementation in HIV disease. This article summarizes a presentation by Stephen A. Spector, MD, at the IAS-USA continuing medical education program held in Chicago in April 2010.