Since 1996 indinavir in combination with zidovudine + lamivudine has been the standard regimen in the treatment of HIV infection. Although protease inhibitor (PI) containing therapies are very potent, many problems have now been identified that reduce quality of life such as a high pill burden, multiple daily dosing and dietary constraints. In addition, adverse events, such as lipodystrophy and lipid metabolism changes are being reported more frequently as long-term experience with PI therapy is gained. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be potent partners for antiretroviral combined therapies. Efavirenz is one of the most recent NNRTIs to be developed. Evidence to date suggests that given its potency, convenience and tolerability, efavirenz will have a major role to play in first-line, PI-sparing regimens and long-term suppressive therapy. However, many questions remain unanswered and future research should attempt to address these issues.