Almost 30 years ago it was proposed that the selection for antiviral drug resistance should be used as an indicator of antiviral drug activity. In addition to discriminating between cellular toxicity and specific activity directed against a viral target, drug resistant mutants have been used to confirm the mechanism of action of antiviral drugs, to discover the functions of several viral proteins and to provide insights into viral evolution and fitness. Drug resistance has also become a standard component of both the preclinical and clinical drug development process. For HIV and increasingly for other viruses drug resistance testing has become standard-of-care in clinical practice. A few selected examples are provided to illustrate each of these points.