While reactive oxygen species (ROS) is generally considered harmful, a relevant amount of ROS is necessary for a number of cellular functions, including the intracellular signal transduction. In order to deal with an excessive amount of ROS, organisms are equipped with a sufficient amount of antioxidants together with NF-E2-related factor-2 (NRF2), a transcription factor that plays a key role in the protection of organisms against environmental or intracellular stresses. While the NRF2 activity has been generally viewed as beneficial to preserve the integrity of organisms, recent studies have demonstrated that cancer cells hijack the NRF2 activity to survive under the oxidative stress and, therefore, a close check must be kept on the NRF2 activity in cancer. In the present review, we briefly highlight important progresses in understanding the molecular mechanism, structure, and function of KEAP1 and NRF2 interaction. In addition, we provide general perspectives that justify conflicting views on the NRF2 activity in cancer.