Interpreting the results of plasma human immunodeficiency virus type 1 (HIV-1) genotypic drug-resistance tests is one of the most difficult tasks facing clinicians caring for HIV-1—infected patients. There are many drug-resistance mutations, and they arise in complex patterns that cause varying levels of drug resistance. In addition, HIV-1 exists in vivo as a virus population containing many genomic variants. Genotypic-resistance testing detects the drug-resistance mutations present in the most common plasma virus variants but may not detect drug-resistance mutations present in minor virus variants. Therefore, interpretation systems are necessary to determine the phenotypic and clinical significance of drug-resistance mutations found in a patient's plasma virus population. We describe the scientific principles of HIV-1 genotypic-resistance test interpretation and the most commonly used Web-based resources for clinicians ordering genotypic drug-resistance tests.