Highly active antiretroviral therapy (HAART) has dramatically reduced mortality and morbidity in HIV-infected persons in developed countries. Although the use of HAART remains limited in Africa, there are global efforts to make available these drugs to several million HIV-infected persons on the continent. In this review we examine the impact of HIV genetic diversity on the occurrence of drug-resistance mutations among non-B subtypes, and discuss the implication of resistant strains in programs aimed at implementing antiretroviral treatment (ART) in Africa, with respect to factors that may favor the occurrence of treatment-acquired drug-resistant viruses, ways to monitor for drug resistance, and strategies to limit its occurrence. We assert that antiretroviral drug resistance is an inevitable consequence when providing long-term treatment, and should not be seen as a limitation of providing antiretrovirals to patients in resource-poor settings, but rather a necessary challenge to be incorporated into the rational design of programs that provide ART in Africa.