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Patients infected with HIV-1 of subtype other than B (‘non-subtype B’) or with HIV-2 are being treated with antiretroviral drugs in increasing numbers. In addition, healthcare providers and laboratory workers working with clinical specimens or animals infected with HIV, SIV or SHIV are at risk of being exposed to the virus and might require post-exposure prophylactic treatment. Thus, it is important to understand the inherent antiviral susceptibility of non-subtype B HIV-1, HIV-2 and SIV to currently available antiretroviral drugs, which have been developed with subtype B HIV-1-infected patients as the primary target population. In addition, knowledge about the consequences of treatment failure in non-subtype B HIV-1- and HIV-2-infected patients, with respect to the development of drug resistance, is crucial for designing optimal treatment strategies. This review summarizes the current state of knowledge in these areas. Non-subtype B group M HIV-1 appears to be susceptible to available agents, but follows several unique pathways to resistance to some drugs that have important clinical implications. Group O HIV-1 is naturally resistant to the non-nucleoside reverse transcriptase inhibitors (NNRTIs). HIV-2 and SIV sm are also naturally resistant to the NNRTIs as well as the protease inhibitor amprenavir. More research into the clinical responses to existing drugs and interpretation of genotypic information is needed, as well as development of diagnostic assays specific for non-subtype B HIV-1 and HIV-2.