Resistance development is a major obstacle to antiviral therapy, and all active antiviral agents have shown to select for resistance mutations. Aspects of antiviral resistance development are discussed for specific compounds or drug classes in the previous chapters, while this chapter provides an overview regarding the evolution of different viruses (HIV, HBV, HCV, and Influenza) under pressure of antiviral therapy. Virus replication is an error prone process resulting in a large number of variants (quasispecies) in patients. Resistance evolution under suboptimal therapy can be schematically distinguished into three phases. (1) preexisting variants less sensitive to the respective drug are selected from the quasispecies population, (2) outgrowing variants acquire additional mutations increasing their resistance, and (3) compensatory mutations accumulate to overcome the generally reduced replica-tive capacity of resistant variants. Successful therapy should be aimed at suppression of all existing viral variants, thus preventing selection of minority species and their subsequent evolution. This implies that the amount of mutations required for first escape to the viral regimen (genetic barrier) should be larger than the expected number of mutations present in viruses in the quasispecies. Accordingly, combination therapy can achieve complete inhibition of replication for most HIV, HBV, and Influenza infected patients without resistance development. However, resistant viruses can become selected under circumstances of suboptimal antiviral therapy and these resistant viruses can be transmitted. Proper use of drugs and worldwide monitoring for the presence and spread of drug resistant viruses are therefore of utmost importance.