The past few years have seen dramatic advances in the treatment of metastatic renal cell carcinoma (RCC). Dissection of the molecular pathways that regulate proliferation, apoptosis, and angiogenesis has led to the development of targeted therapies such as the receptor tyrosine kinase inhibitors sunitinib and sorafenib, the anti-vascular endothelial growth factor antibody bevacizumab, and a class of rapamycin analogues including everolimus and temsirolimus. Each of these agents has demonstrated clinical efficacy in patients with metastatic RCC. The challenge before us is to expand on these successes by identifying which patients will best respond to these targeted therapies, optimizing the proper combination or sequence of available therapies, developing agents with improved side effect profiles, and identifying novel therapeutic targets to expand our armamentarium in the treatment of RCC.