The transcription factor Nrf2 plays paradoxical roles in cancer biology. Transient Nrf2 activation can protect against cancer development, but permanent Nrf2 activation promotes progression and treatment resistance. Persistent activation can be triggered by Keap1-inactivating mutations that cause Nrf2 nuclear accumulation and/or by mutations in the ETGE and DLG motifs of Nrf2, which are important regions for Nrf2–Keap1 interaction. Epigenetic silencing of Keap1 and disruption of the Nrf2–Keap1 interaction by other proteins can also aberrantly activate Nrf2. Given the detrimental effects of excessive activation, pharmacologically balancing Nrf2 activity is a promising avenue for cancer treatment. Numerous Nrf2 activators have been discovered or developed, such as the synthetic compound oltipraz (OPZ) and the plant-derived compound curcumin (CUR). In general, Nrf2 activators can promote the functions of antioxidants, phase II detoxification factors, and transducers. In contrast, only a few Nrf2 inhibitors have been discovered, such as luteolin, ascorbic acid (AScA), and trigonelline (Trg). The existing inhibitors can indirectly downregulate drug detoxification/elimination enzymes and thus sensitize cancer cells to chemotherapy. Overall, using Nrf2 regulators to fine-tune Nrf2 activity levels may help improve patient prognoses. However, more compounds are needed to expand the suite of options for patients.