Since the introduction of HIV protease inhibitors (PIs), disorders of glucose and lipid metabolism have emerged. In dissecting out the direct effect on lipid and glucose metabolism, it has become apparent that individual PIs have different effects on metabolism. Some PIs such as indinavir acutely induce insulin resistance. PIs have also been shown to cause other disorders of glucose metabolism, including impairment of insulin secretion and increased endogenous glucose production. Individual PIs also have different effects on lipid metabolism. Ritonavir predominantly increases triglyceride and very low-density lipoprotein cholesterol levels. Limited studies in HIV-negative volunteers suggest that several of the PIs do not increase low-density lipoprotein cholesterol levels. This review examines the direct effects of PIs on glucose and lipid metabolism by assessing prospective studies of HIV-infected and healthy normal volunteers, and in vitro studies.