Metastatic renal cell carcinoma (RCC) has a highly variable natural history and carries a dismal prognosis. Unlike many other tumors, RCC is generally unresponsive to cytotoxic, hormonal, and radiation adjuvant therapies after cytoreductive surgery. Different modalities of treatment have been tried and tested with modest success. Until recently, only immunotherapies such as interleukin-2 and interferon-alpha have been shown to provide a response, albeit in a minority of patients and often with severe treatment-associated toxicities. Other adjuvant therapies, such as active specific immunotherapy with Bacillus Calmette-Guerin and autologous renal tumor cell vaccines, have not provided alternative solutions. Recent approaches include heat-shock protein peptide complex 96 vaccine and cG250 monoclonal antibody therapy. Novel targeted therapies have been developed using our knowledge of the molecular genetics that belie RCC. This culminated in sorafenib and sunitinib, the first Food and Drug Administration-approved drugs for RCC in more than a decade in the United States. The future will see further trials being carried out in the development of targeted therapies with emphasis placed on patient selection. Staging systems will need to be updated to integrate molecular biomarkers, which could potentially act not just as diagnostic and prognostic predictors, but also as tools for appropriate patient selection for treatment. In the future, this could potentially lead us to our ultimate goal of personalized medicine.