Many factors are involved in the success or failure of antiretroviral therapy. Recent data suggest that there are significant differences in drug absorption and disposition for the protease inhibitor class of antiretroviral drugs, and relationships between plasma concentrations and their antiviral effect have been described. Consequently, the issue of whether therapeutic drug monitoring should be employed for patients receiving treatment with these drugs has arisen. Several criteria must be met before a drug is considered a candidate for therapeutic drug monitoring. These criteria include pharmacological, clinical, and analytic components. Although not all the necessary criteria have yet been met, some of these components have been defined, and additional data are being generated. However, prospectively designed clinical trials must be completed to determine if monitoring protease inhibitor plasma concentrations provides additional clinical benefit to the patient.