Drug resistance testing has proven its use to guide treatment decisions in HIV-1 infected patients. Genotyping is the preferred technique for clinical drug resistance testing. Many factors complicate the interpretation of mutations towards therapy response, such that an interpretation system is necessary to help the clinical virologist. No consensus interpretation exists to date and experts often have quite different opinions. As a result, several algorithms for the interpretation of HIV-1 genotypic drug resistance information have been designed. Clinical evaluation of their genotypic interpretation is not always straightforward. We describe a few publicly available systems and their clinical evaluation. We also stress that in addition to drug resistance, for effective management of HIV infection the clinician needs to take into account all potential causes of treatment failure. Successful therapy heavily relies on the expertise of the clinician.