Starting from cytokines (high-dose interleukin 2 and interferon-α), with poor results, the systemic treatment of metastatic ccRCC evolved with the introduction of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), mechanistic target of rapamycin inhibitors (mTORIs), and immune checkpoint inhibitors (ICIs). This evidence concerns the gene KDR and nonpapillary renal cell carcinoma.