The gold standard therapy for localized clear cell renal cell carcinoma (ccRCC) is surgery while metastatic ccRCCs are treated with systemic therapies. Immune checkpoint and tyrosine kinase inhibition are the main therapeutic strategies for metastatic ccRCCs. They have substantially improved the prognosis of patients with metastatic ccRCC. However, a substantial number of patients never respond or develop resistance mechanisms against standard of care therapies after an initial response to these treatments. Thus, examinations of alternative therapy targets are still an issue of utmost importance although much progress has been made in ccRCC therapy during the past few years.