Retroviral vectors constructed to contain the herpes simplex virus thymidine kinase (HSV-TK) gene were used for transduction of this gene into murine sarcoma and lymphoma cells to yield sublines susceptible in vitro to the cytotoxicity of ganciclovir, a drug specifically activated by HSV-TK. In vivo, ganciclovir induced complete, durable regressions in most mice bearing transplanted HSV-TK-positive sarcomas; its efficacy against lymphomas was only marginal, possibly because of their greater instability of gene expression. The results imply the potential value of an anticancer strategy entailing the prophylactic use of retroviral vectors to create tissue mosaicism for drug sensitivity.