Anti-HIV therapy is characterized by the chronic administration of antiretrovirals (ARVs), and consequently, several problems can arise during the management of HIV-positive patients. ARV disposition can be simulated by combining system data describing a population of patients and in vitro drug data through physiologically based pharmacokinetic (PBPK) models, which mathematically describe absorption, distribution, metabolism and elimination. PBPK modeling can find application in the investigation of clinically relevant scenarios, while providing the opportunity for a better understanding of the mechanisms regulating drug distribution. In this review, we have analyzed the most recent applications of PBPK models for ARVs and highlighted some of the most interesting areas of use, such as drug–drug interaction, pharmacogenetics, factors regulating absorption and tissue penetration, as well as therapy optimization in special populations. The application of the PBPK modeling approach might not be limited to the investigation of hypothetical clinical issues, but could be used to inform future prospective clinical trials.