KDR and cancer: In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients’ treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.