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With drug-resistant HIV-1 present in at least 10%–20% of new infections in Western countries and in >60% of patients failing antiretroviral therapy (ART), monitoring HIV-1 drug resistance is becoming increasingly important for assessing its impact on therapeutic measures of virus control and for guiding treatment. The sensitivity limitations of conventional bulk genotyping often lead to an underestimation of the total burden of drug resistance in a patient, as resistant variants escape detection when present at low frequency within the viral quasispecies. Using sensitive resistance testing methods, a few investigators have linked low-frequency mutations to poor treatment outcomes, while other studies have shown no correlation. Understanding the technical limitations of sensitive testing methods and the relevance of the amount of a particular resistance mutation in the context of different ART regimens will help to define the clinical benefit of low-frequency resistance testing. Paramount to interpreting the clinical utility of sensitive testing is evaluating resistance mutations selectively, at biologically significant frequencies, and using methods that have been broadly validated on clinical specimens.