The tumor microenvironment is determined by the interactions between host and tumor cells, a process in which cytokines play a major role. We have used retroviral vectors to insert and express cytokine genes in tumor cells so as to induce predictable changes in the host cells that infiltrate tumors. This frequently caused changes in tumor cell phenotype through autocrine/intracrine pathways. We reasoned that cytokine-induced alterations in tumor cell phenotype and/or in infiltrating host cells might alter the in vitro and in vivo cellular response to irradiation. In the present paper we document some of the effects of expression of interleukin-6 (IL-6) and IL-7 genes in tumor cells in this regard. The studies support the hypothesis that cytokines may play a role in determining both intrinsic tumor radioresponsiveness and the tumor microenvironment and in these ways may influence in vivo tumor irradiation responses. Possible cytokine gene-mediated approaches to radiotherapy cancer are discussed.