Nevirapine and efavirenz are nonnucleoside reverse transcriptase inhibitors used in antiretroviral regimens to treat HIV infection. Therapeutic drug monitoring in patients on antiretroviral regimens that include these agents has been suggested to be beneficial in terms of efficacy and toxicity. Various analytical methods are available to quantify nevirapine and efavirenz concentrations. A previously published, nine-step, decision-making algorithm has been used to evaluate the utility of therapeutic drug monitoring of efavirenz and nevirapine. A relationship has been found between efavirenz concentrations and toxicity and between nevirapine concentrations and virological efficacy. For efavirenz, the recommended therapeutic range is 1-4 mg/L; for nevirapine, minimum trough concentrations of >3.4 mg/L have been suggested. Both drugs have demonstrated interindividual pharmacokinetic variability. The pharmacokinetic parameters of nevirapine vary in female patients, patients coinfected with hepatitis B virus, and patients from different geographical locations. The pharmacokinetic parameters of efavirenz have also been shown to vary depending on patients' race, baseline bilirubin level, and geographical location. Drug interactions and resistance mutations can also be confounders in the pharmacokinetic parameters of these drugs. Coinfection with hepatitis C can also contribute to increased drug concentrations. The risk of hepatotoxicity can be increased in the presence of elevated nevirapine concentrations. As patients with HIV-1 infection will be managed with different combinations of antiretroviral regimens over the course of their lives, the limitations of having only four drug classes from which to choose make it even more important to maximise the usefulness of each of these drug classes. The available evidence suggests that therapeutic drug monitoring of efavirenz and nevirapine may contribute to the clinician's ability to evaluate efficacy and safety in patients taking these drugs. Patients at risk of toxicity from drug interactions or disease interactions and patients who may be noncompliant may gain the greatest benefit from therapeutic drug monitoring of efavirenz and nevirapine.