Highly active antiretroviral therapy (HAART) has led to a reduction in HIV-related mortality and morbidity. Most patients who have benefited from HAART are infected with HIV-1 subtype B, which predominates in Western Europe, the USA and the rest of the industrialised world. However, most HIV-infected people live in sub-Saharan Africa, Asia and Eastern Europe. In these areas, subtypes other than B are responsible for the epidemic of HIV-1 infection. This review focuses on the clinical significance of HIV-1 infection with a non-B subtype. The increase in availability of HAART to developing countries together with the large number of HIV-1-infected immigrants being treated in the industrialised world means that data on the clinical response to therapy for non-B HIV-1 infections are becoming of greater practical relevance. If antiretroviral agents, which generally target subtype B, are less efficacious in non-B infections, this will have major clinical implications for therapeutic strategies. Data on drug susceptibility, clinical response and the development of resistance in non-B HIV-1 subtypes are discussed here.