Even if, to date, there are a few in vivo studies that demonstrate the effectiveness of targeting the Nrf2 pathway, the studies reported in this review suggest that not only could the modulation of Nrf2/KEAP1 pathway represent a valid strategy to counteract RCC progression but combining compounds with chemotherapeutic agents could also enhance the response to chemotherapy in clinical settings. The gene discussed is NFE2L2; the disease is renal cell carcinoma.