The recent development of new antiretroviral drugs, along with the evolution in clinical practice guidelines that include the recommendation of the use of three- to four-drug combination regimens for achieving optimal suppression of viral replication, has focused clinicians on the relevance of drug-drug interactions in the chronic care of HIV-infected individuals. However, the routine clinical management of drug interactions is complicated by our expanding knowledge of the physiologic mechanisms underlying pharmacokinetic interactions, particularly as they relate to drug transport and tissue distribution (eg, P-glycoprotein) and biotransformation (hepatic cytochrome p450 mono-oxygenase induction and inhibition). This review provides an updated summary of key drug interactions that have been reported since its initial publication.