The development of antiretroviral therapy has led to a major reduction in human immunodeficiency virus (HIV)-related mortality. There are now six antiretroviral drug classes, with more than 20 unique antiretroviral drugs. However, HIV drug resistance occurs with all antiretroviral agents. Drug resistance can affect the response to antiretroviral therapy and is associated with increased mortality. The emergence of resistance in persons on antiretroviral therapy and the transmission of drug-resistant HIV strains to newly infected persons are now major public health concerns. Resistant variants that make up as little as 1% of the viral population in an HIV-infected person are clinically important, as they can rapidly grow under drug selection pressure and lead to therapy failure. However, current resistance assays used in the clinic reliably detect resistant variants only if they make up at least 20% of the circulating viral population. Recently, antiretroviral drugs have been developed that can inhibit HIV replication at new sites within the viral life cycle. These new drugs may improve clinical outcomes in persons infected with multidrug-resistant HIV. This review addresses the epidemiology and biological mechanisms of HIV drug resistance and the new approaches to detect and combat HIV drug resistance.