Increasing evidence indicates that antiretroviral drug resistance is associated with impaired viral fitness and that this impairment can translate, at least transiently, into a virological and immunological benefit. The optimal strategies for exploiting the fitness cost associated with drug resistance remain to be determined. For highly drug-experienced patients receiving salvage therapy with a detectable viral load and with limited or no remaining drug options, continuing the current regimen may be a useful strategy to delay disease progression. In this context, it remains controversial whether it is preferable to continue failing therapy with nucleoside reverse transcriptase inhibitors, protease inhibitors or both.