We describe an EBV-driven lytic system (LySED) that can be used to specifically target therapy to EBV-containing tumors. This system takes advantage of the transactivating properties of EBNA-1, a latency protein expressed in all EBV-containing cells, to drive the expression of Zta, a gene sufficient for inducing the EBV lytic cycle. Thus, EBV provides both the target and the executor for mediating tumor-specific cell death, markedly increasing the specificity of the system. Transfection of EBV-positive cell lines with the LySED construct resulted in a switch to lytic cycle and subsequent cell death, even in the presence of an inhibitor of EBV thymidine kinase (acyclovir) without an increase in virion production. In contrast, growth of EBV-negative B-cell lines was not affected.