Recent advances in understanding the molecular events associated with renal cell carcinoma (RCC) are revolutionizing the therapeutic options offered for patients with advanced-stage RCC. These targeted approaches for RCC are based primarily on antiangiogenesis and/or specific kinase inhibitors targeting the vascular-endothelial growth factor and platelet-derived growth factor receptors, Raf and mammalian target of rapamycin inhibitor. In this context, characterization of the molecular events unique to RCC is also of critical significance for gene therapy endeavors. The attributes of gene therapy for RCC may include true targeting to cancer cells, transfer of immunomodulatory or antiangiogenic genes and novel nonapoptotic cancer cell killing mechanisms. Gene therapy may thus become a promising new adjuvant modality for RCC and expand the therapeutic armamentarium against RCC. Beyond the current stage of preclinical proof of principle and toxicological analysis in animal models, the utility of RCC gene therapy will depend on safety and efficacy trials in human subjects. These trials will determine whether targeted therapy for RCC employing genome-based strategies will broaden the current therapeutic spectrum for RCC comprising kinome-based, immunomodulatory and antiangiogenesis strategies.