Treatment of HIV-1 with antiretroviral therapy may select mutations in the pol gene associated with resistance to reverse transcriptase inhibitors and protease inhibitors. To provide durable clinical benefit, emergence of drug resistance is countered by prescription of alternative drug regimens. Data on sequential treatments that are effective after virologic failure and the selection of drug resistance is largely confined to HIV-1 subtype B, the clade that has circulated in North America and Europe. However, HIV-1 subtype B currently accounts for only 12% of the estimated 40 million HIV infected individuals worldwide. The global HIV-1 epidemic includes infection with nine identified HIV-1 group M subtypes (A-K), as well as distinct sub-subtypes and numerous chimerical or recombinant forms. Increasing access to treatment of HIV-1 in the developing world and increasing non-subtype B infection through travel and migration pose new questions about the susceptibility and response of these diverse HIV-1 viruses to antiretroviral drugs. Here we review HIV diversity and the published literature on drug resistance, comparing the known resistance mutations in individuals infected with subtype B to the growing experience in the treatment of non-subtype B HIV-1 worldwide.