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Human immunodeficiency virus type 1 (HIV-1) drug resistance genotyping is recommended to help in the selection of antiretroviral therapy and to prevent virologic failure. There are several ultrasensitive assays able to detect HIV-1 drug-resistance minority variants (DRMVs) not detectable by standard population sequencing-based HIV genotyping assays. Presence of these DRMVs has been shown to be clinically relevant, but its impact does not appear to be uniform across drug classes. In this review, we summarize key evidence for the clinical impact of DRMVs across drug classes for both antiretroviral treatment-naive and antiretroviral treatment-experienced patients, and highlight areas where more supporting evidence is needed.