The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically during the past few years. Sunitinib malate, sorafenib tosylate, bevacizumab with interferon α, temsirolimus, and everolimus have improved clinical outcomes in randomized phase 3 trials by inhibiting the vascular endothelial growth factor and related pathways. Combinations and sequences of these agents are being evaluated. Other novel agents are in clinical development, some of which target novel pathways not yet exploited as therapy for RCC. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC. Cancer 2009;115(10 suppl):2361-7. © 2009 American Cancer Society.