The HIV-1 protease inhibitors (PIs) are widely used in combination antiretroviral therapy for the management of HIV-1 infection. Certain characteristics of the PIs, in particular their metabolism being mainly via the cytochrome P450 isoenzyme group and their gastric absorption being pH dependent, make them prone to clinically significant drug interactions with other antiretrovirals, concomitant medication and complementary treatments. Owing to the nature of the disease, individuals with HIV are frequently prescribed complex treatment regimens (both for the management of intolerance, toxicity and viral resistance to antiretroviral therapy, and in the management of co-morbid states) that may interact with PI therapy. For many of these potential interactions, few data are available. This review will focus on the current use of PIs, highlighting some important management issues encountered with common pharmacokinetic interactions seen in clinical practice.