In a very short period of time, availability of antiretroviral drugs has increased from one drug with very modest activity to 12 approved drugs with remarkable potency, particularly when used in combination. The additional availability of absolutely quantitative assays with a broad dynamic range to measure plasma HIV-1 RNA has dramatically changed the evaluation of these new antivirals and the management of patients infected with the human immunodeficiency virus (HIV). The approved antiretroviral drugs represent three novel classes including nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors as well as protease inhibitors. Clinical trials evaluating different combinations of these drugs have resulted in the generation of some basic guidelines for their appropriate use. These guidelines focus on using these drugs in complex, multidrug regimens with the ultimate goal to keep the viral burden, as measured by plasma viral RNA levels, as low as possible and for as long as possible on a drug regimen that is compatible with long-term tolerance and compliance. To maximize the potential of these new drugs and to avoid significant associated toxicities and drug interactions, the treating physician must be completely aware of the pharmacokinetics and unique antiviral properties of these drugs. This review focuses on these unique properties as well as provides general guidelines for their appropriate use.