Guidelines for use of antiretroviral agents presently recommend first-line treatments with nonnucleoside reverse transcriptase inhibitor-based regimens. Efavirenz is the standard-of-care comparator for nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. As with many antiretroviral medications, efavirenz is subject to interindividual variation in metabolism, effectiveness, and tolerability. Demographic factors such as age, sex, and ethnicity have been demonstrated to influence this variability, but other underlying factors such as genetics, disease state, and concomitant drug use can also play a role. The clinical impactions of these factors are only beginning to be understood. Although significant advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of efavirenz, providers should not withhold treatment of HIV infection with an efavirenz-based regimen on the basis of racial or ethic categorizations.