There are 20 antiretroviral agents approved by the US Food and Drug Administration (FDA), four of which were approved in 2003. With 20 antiretrovirals FDA-approved, interactions occur when the medications alter the toxicity profile or efficacy of the other medication. In order to maintain clinical relevance, only the most significant interactions published within the past 12 months are highlighted in this article. Interactions discussed involve atazanavir, fosamprenavir, lopinavir/ritonavir, tenofovir, proton pump inhibitors, H₂-blockers, clarithromycin, and vardenafil. Important interaction-management strategies also are discussed. The field of HIV pharmacology is constantly advancing, as are the drug interaction data. To screen, manage, dose adjust, and counsel, the physician and other health care professionals are highly advised and encouraged to consult with an infectious disease clinical pharmacist when managing patients receiving highly active antiretroviral therapy.