Owing to the improved longevity afforded by combination antiretroviral therapy (cART), HIV-infected individuals are developing several non-AIDS-related comorbid conditions. Consequently, medical management of the HIV-infected population is increasingly complex, with a growing list of potential drug-drug interactions (DDIs). This article reviews some of the most relevant and emerging potential interactions between antiretroviral medications and other agents. The most common DDIs are those involving protease inhibitors or non-nucleoside reverse transcriptase inhibitors, which alter the cytochrome P450 enzyme system and/or drug transporters such as p-glycoprotein. Of note are the new agents for the treatment of chronic hepatitis C virus infection. These new classes of drugs and others drugs that are increasingly used in this patient population represent a significant challenge with regard to achieving the goals of effective HIV suppression and minimization of drug-related toxicities. Awareness of DDIs and a multidisciplinary approach are imperative in reaching these goals.