Minor drug-resistant variants exist in every patient infected with human immunodeficiency virus (HIV). Because these minority variants are usually present at very low levels, they cannot be detected and quantified using conventional genotypic and phenotypic tests. Recently, several assays have been developed to characterize these low-abundance drug-resistant variants in the large, genetically complex population that is present in every HIV-infected individual. The most important issue is what results generated by these assays can predict clinical or treatment outcomes and might guide the management of patients in clinical practice. Cutoff values for the detection of these low-abundance viral variants that predict an increased risk of treatment failure should be determined. These thresholds may be specific for each mutation and treatment regimen. In this review, we summarize the attributes and limitations of the currently available detection assays and review the existing information about both acquired and transmitted drug-resistant minority variants.