Treatment with antiretroviral drugs such as the HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors have contributed to the improvement of life of many HIV-infected patients in recent years, but antiretroviral therapy is not without problems. In some patients, treatment is not effective and suppression of viral replication is not achieved. Other patients experience toxicity and have to stop treatment or change to a less effective treatment. Several studies have demonstrated a relationship between plasma concentrations of the protease inhibitors and non-nucleoside reverse transcriptase inhibitors and viral suppression and toxicity. Therapeutic drug monitoring uses drug concentrations to individualize and optimise therapy by dosage adjustments and many clinicians have advocated for the use of therapeutic drug monitoring in HIV antiretroviral therapy. Evidence from a number of randomized clinical trials supports the use of therapeutic drug monitoring, but the studies have limitations and might not apply to all the antiretroviral drugs. However, the consensus is that certain patients are very likely to benefit from therapeutic drug monitoring. Additionally, the combination of therapeutic drug monitoring and genotypic or phenotypic resistance testing might further improve antiretroviral therapy.