Efavirenz is a non-nucleoside reverse transcriptase inhibitor that in most treatment guidelines is recommended to be taken combined with two nucleoside analogue reverse transcriptase inhibitors, as a preferred first-line regimen for the treatment of HIV-1 infection. The antiretroviral efficacy of efavirenz-based combination regimens is good, as has been demonstrated in many clinical trials. Efavirenz has a long plasma half-life, which allows for once-daily dosing, but, as a consequence of this and the low genetic barrier, it is also prone to select for viral resistance when adherence to therapy is suboptimal. The most frequently encountered side effects are neuropsychiatric symptoms. These side effects are usually transient, but have been shown to persist for up to 2 years after initiation of therapy in some patients. This review outlines important and recent pharmacological and clinical data, which explain why efavirenz became a component of preferred treatment regimens today.