In recent years an improved understanding of renal cell carcinoma (RCC) tumor biology has translated into major advancements in the treatment of patients with metastatic RCC. These novel therapies include inhibitors of the vascular endothelial growth factor (VEGF) pathway, and inhibitors of the mammalian target of rapamycin (mTor) pathway. In contrast to the results seen with molecularly targeted therapies, the administration of high-dose bolus IL-2 (HD IL-2) can produce durable responses in a small percentage of patients. While the substantial toxicity and limited efficacy that is associated with HD IL-2 limits its application, novel immunotherapies may be able to produce durable benefit with less toxicity. Once the standard of care, the role of low-dose single-agent cytokines is now limited in patients with RCC. However, combinations of cytokines with targeted therapy may have merit. The advent of targeted therapy in RCC does not eliminate the potential utility of immunotherapy but rather requires a rational refinement of this approach through improvements in patient selection and combination therapy that may increase the cure rate for patients with this disease.