For several decades, metastatic renal cell carcinoma (mRCC) was considered resistant to therapy and thus linked to poor prognosis. Recent years have seen a complete revolution of the therapeutic landscape, with the introduction of new target therapies that have radically changed treatment strategies in this setting. These new agents have proved to be effective if directed mainly against the angiogenic pathway. The vascular endothelial growth factor family is, in fact, the main target of a number of new drugs, such as monoclonal antibodies and different generations of tyrosine-kinase inhibitors that are currently approved or in different stages of clinical trial for the treatment of mRCC patients.