Protease inhibitors (PIs) have become a crucial element in the treatment of patients infected with HIV. However, the widespread use of PI therapy has also been associated with a number of metabolic adverse effects, including fat redistribution and hyperglycaemia. The objective of this review is a discussion of the incidence, pathophysiology, management and prevention of PI-associated hyperglycaemia. Initial case reports have been followed by large cross-sectional and cohort studies, which demonstrate that the incidence of PI-induced impaired glucose tolerance, as well as frank diabetes mellitus, is significant and demands attention. Investigations into the pathophysiology behind PI-associated hyperglycaemia have identified an underlying problem of insulin resistance that is presumably caused by both direct PI-induced mechanisms and lipotoxicity. Given this, clinical trials have explored the use of various classes of oral hypoglycaemic agents in the management of PI-induced diabetic complications, and the use of insulin therapy must be considered as well. Newer PI agents are also under development, with the hope of reducing metabolic adverse effects. In the meantime, prevention, in the form of dietary modification, regular physical activity and periodic screening for impaired glucose tolerance, must receive heightened attention in the care plan of patients receiving long-term PI therapy.