In recent years, the management of metastatic renal cell carcinoma (mRCC) has been revolutionized by the advent of targeted therapies. Multitargeted kinase inhibitors (such as sunitinib, sorafenib, pazopanib, and axitinib), the vascular endothelial growth factor inhibitor bevacizumab, and mammalian target of rapamycin inhibitors (such as everolimus and temsirolimus) have become the standard of care for the palliation of metastatic disease. Unfortunately, cumulative toxicities and the lack of marked benefits have prevented the combined use of most molecularly targeted agents. Selected patients with mRCC benefit from immunotherapy, as subsets of patients can experience long-term disease remission or complete response with high-dose interleukin-2. In order to optimize the value of immunotherapy, improvements in the selection of drugs and combinations with novel immunomodulatory agents must be pursued.