Efavirenz, the potent, once-daily non-nucleoside reverse transcriptase inhibitor, has been successfully used since 1996 and is still a cornerstone of antiretroviral therapy for use in treatment-naïve, treatment-experienced and difficult-to-treat patients. The efficacy of efavirenz in these patient groups has been established in many clinical and cohort studies. Furthermore, efavirenz is now available as a single 600 mg tablet, providing a simplified therapy and decreased pill burden, which may lead to improved adherence and treatment outcomes. Efavirenz has a well-characterized tolerability profile, the more notable side effects being mainly short-term and non-life-threatening, such as central nervous system disturbances and rash.