Objectives: To address the rationale for anti-angiogenic targeted therapies in advanced RCC. Methods: We reviewed the international recent literature, using Pubmed search. Results: RCC is genetically linked to factors regulating angiogenesis, in particular vascular endothelial growth factor (VEGF). Sunitinib is a multitarget receptor tyrosine-kinase (TK) inhibitor, acting on VEGF receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR). Sorafenib is an oral multikinase inhibitor (VEGFR and PDGFR) showing also inhibitors effect on the Raf system. Phase I trials showed no life threatening toxicities relates to these agents. Phase II and phase III trials showed that these antiangiogenic agents are effective in the treatment of advanced RCC, mainly in cytokine refractory metastatic RCC. Survival benefits exist in particular when advanced RCC patients undergo cytoreductive nephrectomies before the initiation of the systemic therapy. To better use this kind of targeted therapy in advanced RCC, different points must be developed: the identification of clinical characteristic of RCC able to predict outcomes and responses to therapy; differences among different compounds; advantages of combination or sequential therapies. Conlusions: Targeted therapy with Sunitinib and Sorafenib has been approved to FDA and is revolutioning how we clinically approach advanced RCC.