Gene therapy strategies for cancer currently aim at targeting gene delivery to the malignant cell. In a mouse model of intracerebral Lewis lung carcinoma (3LL), adenoviral vectors transduce not only 3LL cells but also brain parenchymal cells including endothelial cells, neurons, microglia, and astrocytes~ in vivo~. Furthermore, transgene expression persists longer in brain than in tumor. Transfer of IFN-γ into brain parenchymal cells rather than tumor is both necessary and sufficient to generate antitumor therapeutic benefits. Therefore, parenchymal cells represent an effective and necessary target for delivery of genes that render the brain uninhabitable by the tumor.