Drug transporter proteins play a crucial role in drug disposition. The P-glycoprotein drug efflux transporter is a determinant of oral bioavailability and central nervous system (CNS) penetration of protease inhibitors (PIs), and may affect drug penetration to other tissue compartments that can serve as sanctuaries for HIV. Potent and selective inhibitors of P-glycoprotein can dramatically increase PI CNS penetration. Polymorphisms in the MDR1 gene regulating P-glycoprotein expression are associated with differences in drug disposition, with some data indicating that different genotypes are associated with differences in plasma PI levels and magnitudes of CD4+ cell count recovery under therapy. The activity of drug transporters in modulating antiretroviral drug effects and the potential for exploiting this activity to maximize therapeutic benefit and minimize drug toxicity are the subjects of ongoing study. In addition, inhibition of transporter proteins may increase the risk of hepatotoxicity and other adverse drug effects and is being investigated. This article summarizes a presentation given by Richard B. Kim, MD, at the March 2003 International AIDS Society-USA course in Atlanta.