Protease inhibitors (PIs) are widely assumed to be associated with a syndrome of insulin resistance accompanied by hyperlipidemia and fat redistribution. Insulin resistance in HIV infection has numerous other causes, however, which include not only the direct effects of antiretroviral drugs but also factors such as aging and restoration to health accompanied by fat accumulation. Studies of PIs in HIV-infected and noninfected patients indicate that some of these drugs are associated with reduced insulin sensitivity (greater acute versus chronic effects) that may be due to direct blockade of the insulin-sensitive glucose transporter in muscle and fat cells. Other studies have shown that insulin levels increase over time with antiretroviral therapy, likely the result of improved health, fat accumulation, and aging, and that increases in visceral fat and upper trunk fat are associated with a higher risk of insulin resistance in HIV-infected and -uninfected individuals alike. This article summarizes a presentation on insulin resistance in HIV infection made by Carl Grunfeld, MD, PhD, at the 10th Annual Ryan White HIV/AIDS Program Clinical Update in Phoenix in June 2007.