Nucleoside antIviral drugs, such as AZT and acyclovir, must be phosphorylated by thymidine kinase before incorporation into DNA. Their effectiveness for antiviral therapies is based on the lower substrate specificity of the viral form of the enzyme, compared with the human form. In this issue, Christians et al. describe their use of a form of directed DNA evolution, called DNA family shuffling, to enhance the ability of the herpesvirus thymidine kinase to phosphorylate AZT (p. 259). The end product was a newly evolved "super" thymidine kinase, which had an increased ability to phosphorylate AZT, making Escherichia coli that express the enzyme susceptible to greatly reduced amounts of AZT.