The availability of potent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens for antiretroviral therapy and concerns regarding protease inhibitor (PI)-related metabolic disturbances have led to significant shifts in treatment practices in HIV infection. NNRTI-based regimens may have several advantages over PI-based therapy for initial or prolonged therapy, including more convenient administration regimens, lower tablet volume, fewer drug interactions, and central nervous system penetration. No data from prospective clinical trials currently exist comparing the 3 approved agents (efavirenz, nevirapine or delavirdine). Both efavirenz and nevirapine have been compared to triple therapy with the PI indinavir over 48 weeks as initial therapy, with similar responses being observed with nevirapine regimens and superiority observed with efavirenz. A smaller 24-week study has suggested nevirapine may be superior to the PI nelfinavir. Limited comparative data in patients with high viral loads treated with nevirapine- or delavirdine-based regimens currently exist. However, cohort data and selected patient data from clinical trials suggest comparable activity to PI-based regimens in these patients. The superiority of efavirenz over indinavir-based regimens has been observed in comparative data in a subset of patients with high viral loads. In treatment-experienced patients, available uncontrolled data suggest these agents contribute to regimen efficacy in NNRTI-naïve, treatment-experienced patients. Efavirenz has demonstrated superiority over nelfinavir in nucleoside-experienced patients, although combining these 2 agents may represent the best approach in these circumstances. The tolerability of NNRTIs appears generally good with few individuals discontinuing in clinical studies as a result of adverse drug events. The majority of adverse events with NNRTIs occur within the first month, and are predictable and manageable without therapy interruption.