This chapter describes an approach to destroying malignant cells by effectively changing the tumor phenotype through the delivery of Escherichia coli purine nucleo-side phosphorylase (PNP). In the presence of nucleoside prodrugs, this nonhuman enzyme in purine metabolism causes the death of the transfected (transduced) cells through the release of a highly potent antitumor agent. Importantly, the properties of the liberated compounds kill not only the transfected (transduced) cells but cause the efficient destruction of tumor cells that do not express the gene (i.e., bystander cells). In addition, the cytotoxic agents are active against both proliferating and nonproliferating tumor cells and, therefore, unlike other antitumor agents, this system can target the nonproliferating component of solid tumors. Many common cancers (including prostate, breast, colon, lung, brain, melanoma, pancreas, ovarian, kidney) progress to become untreatable and eventually cause death. Compounds are available that could abolish these tumors, but they are too toxic to systematically administer safely to cancer patients. We have shown that some of these compounds are remarkably potent and can abolish otherwise refractory human cancers when produced within the tumor mass by virtue of expression of E. coli PNP.