Metastatic renal cell carcinoma (RCC) is notoriously chemoresistant; up until recently, immunotherapy (in particular interferon-alpha) has represented the treatment of choice. The understanding of the biology of RCC has resulted in the development of targeted therapies. In particular, multikinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib), antivascular endothelial growth factor agents (bevacizumab), and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) now have a role in the approach to different subsets of RCC. Sunitinib is indicated for the first-line therapy of metastatic RCC as a consequence of a positive phase III trial versus interferon-alpha; sorafenib is now registered for the second-line treatment of RCC, which was earlier treated with cytokine as a consequence of a positive phase III trial versus placebo. Bevacizumab is also indicated in the first-line treatment of metastatic RCC given in combination with interferon-alpha as a consequence of two positive phase III trials. Temsirolimus, unlike the other agents, has also shown activity in poor-prognosis patients, and is now the treatment of choice in previously untreated poor-prognosis RCC as a single agent. Everolimus can be considered as the best therapeutic option in patients with RCC pretreated with targeted agents as a consequence of a positive phase III study versus best supportive care. Markers for appropriate treatment selection, combined use of targeted agents, treatment of special histologies, and adjuvant and neoadjuvant setting represent important special issues to be dealt with in future studies.