Simple SummarySeveral studies showed that oxidative stress is involved in cancer occurrence, development, progression chemoresistance and radio resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays a key role in protecting cells against oxidative damage. Moreover, several studies demonstrated that both natural and synthetic compounds can modulate NRF2/KEAP1 signaling in normal and cancer cells. In this review, we discussed the current literature regarding the role of natural and synthetic compounds in regulating NRF2/KEAP1 signaling pathway in prostate cancer.AbstractProstate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.