Tumor angiogenesis is a complex multistep process, resulting from the imbalance between pro- and antiangiogenic
factors in tumor environment. A crucial role in this process is played by vascular endothelial growth factor
(VEGF). Its expression in metastatic renal cell carcinoma (mRCC) is mostly regulated by hypoxia and it is associated with
the loss of the von Hippel-Lindau (VHL) tumor suppressor gene. The importance of identifying VEGF-independent pathways
in tumor angiogenesis is increasingly recognized as result of the emerging drug resistance to anti-VEGF therapies.
Advances in knowledge of tumor angiogenesis, growth and progression permit to develop new approaches for the treatment
of mRCC, targeting not only VEGF and VEGF tyrosine kinase receptors (VEGFRs) tyrosine kinase pathway, but
also serine/threonine kinases, α5β1-integrin, AKT, PI3K and STAT3. Starting from sorafenib and sunitinib, several agents
have been approved, with a long list of drugs, as well as axitinib, tivozanib, cediranib and VEGF-Trap, presently in course
of evaluation. Here, we illustrate the principal steps of tumor angiogenic process; showing approved anti-angiogenic
agents, the emerging molecules currently under evaluation and some relevant patents.