Genotypic assays are widely used tools for determining human immunodeficiency virus type 1 (HIV-1) drug resistance and for guiding treatment changes in patients failing antiretroviral therapy. Several systems have been developed to interpret the complex influence of key amino acid substitutions of the enzymes targeted by therapy on the phenotypic susceptibility or clinical response to available antiretroviral agents. This overview identifies 21 systems giving an interpretation on how amino acid substitutions affect phenotypic drug susceptibility or clinical activity of anti-HIV-1 agents. There was substantial variability in the mechanisms underlying the interpretations, the nature of the systems, their intended use, the source type of their knowledge base, and their update and output. Most of the systems could be accessed for free on the internet, functioned as rule-based algorithms updated by experts and at least partially based on literature evidence, and offered an automated report through a software. Nevertheless, the rule base was not always clarified. An update of the rules and the clinical validation of the systems are presented to help in the critical evaluation of their possible use. Importantly, only 8 systems were intended for clinical use and 5 of these had at least partially undergone clinical validation.