Resistance-testing technology has been incorporated into the standard of care for human immunodeficiency virus type 1 (HIV-1) infection and therapy with protease and reverse transcriptase inhibitors. Inhibitors of HIV-1 entry represent an emerging mode of antiretroviral therapy, and HIV-1 entry inhibitors encompass three mechanistically distinct classes of agents known as attachment inhibitors, coreceptor inhibitors, and fusion inhibitors. Each class of agent has demonstrated promise in controlled clinical trials, and understanding the determinants and evolution of viral resistance will be critical for the optimal development and deployment of these new treatment classes. Advances in resistance-testing technologies have paralleled the development of HIV-1 entry inhibitor therapies, and the available data support the notion that attachment, coreceptor and fusion inhibitors offer complementary modes of therapy and distinct resistance profiles.