Emergence of drug-resistant viral variants is a major reason why HIV-infected patients experience viral rebound during antiretroviral therapy. Although combination antiretroviral therapy substantially inhibits viral replication, replication-competent mutant virus remains. In addition, it is now clear that virologic failure is not necessarily caused by failure of all drugs in a regimen. The use of resistance-testing data can assist in understanding the reasons for failure of antiretroviral therapy. However, there is a need for additional trials to better define the role resistance testing may play in developing management approaches to mitigate or minimize emergence of resistant HIV.