Metastatic clear cell renal cell cancer has traditionally been treated with cytokines (interferon or interleukin-2). Improved understanding of biology has engendered novel targeted therapeutic agents that have radically altered the outlook. Vascular endothelial growth factor, the related receptor and the mTOR signal transduction pathway have particularly been exploited. Sunitinib malate, sorafenib and temsirolimus have improved clinical outcomes compared with interferon in randomized trials. Other multitargeted tyrosine kinase inhibitors (lapatinib, axatinib and pazopanib) and antiangiogenic agents (bevacizumab and lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. The future of the therapy of renal cancer appears promising owing to the efficacy of these novel agents. Clinical trials designed to further assess these and other agents need to be vigorously supported.