In 1996, the marketing of several new antiretroviral drugs initiated the era of highly active antiretroviral treatment. Although the combination of antiretroviral drugs has considerably reduced the morbidity and mortality associated to HIV infection, HIV therapy presents several issues such as toxicity, drug-drug interactions and suboptimal drug response. We evaluated the use of Therapeutic Drug Monitoring (TDM) for protease inhibitors (PIs) and efavirenz (EFV) as a complementary tool for the clinical follow up of HIV infected individuals. We showed that PIs and EFV have a large inter-patient but a low intrapatient variability in drug levels which make them good candidates for TDM. Reference percentile curves were established for PIs and EFV from concentrations measured in patients with optimal virus suppression to help clinicians interpret a patient’s drug level. The dosage of PIs and EFV proved to be useful in the following clinical situations: suspicion of non adherence, suspicion of toxicity, modifications of physiological parameters, evaluation of drug interactions and virological failure.