The increased awareness of antiviral resistance over the past decade has paralleled the development of new antiviral agents. While such resistant viral isolates are of clinical significance primarily in immunocompromised individuals, the development and transmission of such mutants have been reported in immunocompetent persons as well. As antiviral agents are increasingly utilised by the clinician, the incidence of such occurrences is likely to increase. Issues relating to mechanisms of antiviral resistance, clinical manifestations and significance of resistance, and implications for future antiviral development and utilisation are reviewed in this article. Viruses that are discussed include herpes simplex virus, varicella-zoster virus, cytomegalovirus, influenza A virus, and human immunodeficiency virus.