Antiviral drug resistance can be one of the causes for HIV-1 therapy failure. Several studies have shown some beneficial effect of antiviral resistance testing on response to the following therapy regimen. The technical performances of genotypic and phenotypic assays have been considerably improved with time. However, both are still limited in their power to fully map antiviral resistance as cause of therapy failure. Nevertheless, the results of genotypic and phenotypic assays can often deliver complementary information. The greatest challenge still remains in the accurate interpretation of in vitro resistance results, whether genotypic or phenotypic, into information that can be implemented into clinical practice. For phenotypic assays, bioinformatics analyses linking fold-resistance values and clinical response data have been performed, or are currently ongoing, to assign clinical cut-offs for all drugs. Genotypic drug-resistance interpretation systems have been developed and are continuously being updated to solve the same problem. Retrospective and prospective studies have compared systems in their performance to predict phenotype or in their ability to predict therapy outcome. All these analysis are of value, but still display some weak points. However, due to the fast evolving know-how in the field, a prospective trial in which different systems are compared head-to-head will be difficult to design.