Antiviral drug resistance is an area of increasing clinical importance in treatment of a number of viruses including herpes simplex virus (HSV) and human cytomegalovirus (CMV). Work with these herpesviruses illustrates the value of studies of drug resistance. Novel aspects of drug mechanisms, such as a CMV gene product that contributes to ganciclovir phosphorylation, can be identified via drug resistance mutations. Drug targets such as the HSV DNA polymerase that are involved in drug recognition can be dissected by sequencing of drug-resistance mutations, which can point to alternate therapeutic strategies. Analysis of virus mutants in animal models and in patient populations can help assess the value of viral proteins such as the HSV thymidine kinase and ribonucleotide reductase as drug targets and the pathogenic potential of drug resistant mutants. Such studies reveal a broad spectrum of alterations conferring resistance and emphasize the importance of heterogeneous populations of virus in resistance and pathogenesis and the need to develop alternate therapies.