The impact of HIV-1 subtype on clinical outcome following exposure to antiretroviral therapy is currently not well known. Natural polymorphisms are often present in HIV-1 non-B subtypes at positions known to be associated with drug resistance in clade B viruses. These changes might influence the emergence of drug-resistant viruses, modifying drug susceptibility and/or the virus replicative capacity. Moreover, different pathways may lead to drug resistance according to HIV-1 clade. Finally, the influence of subtype on the performance of phenotypic assays and in the interpretation of algorithms for genotypic resistance is currently a matter of debate. All these aspects explain why the response to antiretroviral therapy might vary in subjects infected with different HIV-1 clades.