The Keap1–Nrf2 pathway is a cellular defense system against oxidative and xenobiotic stresses derived from reactive oxygen species (ROS) and electrophiles, respectively. Nrf2 is a key transcription factor that activates a set of cytoprotective genes, including those encoding antioxidative and detoxifying enzymes. Keap1 is an adaptor protein of Cullin3-based E3 ligase, which regulates Nrf2 activity in response to these stresses. Under unstressed conditions, Keap1 constitutively degrades Nrf2 via the proteasome pathway. Keap1 interacts with Nrf2 through DLGex and ETGE sites in Nrf2 Neh2 domain, which is critical for regulation of Nrf2 degradation. ROS and electrophiles modify cysteine residues of Keap1 to inactivate the ubiquitin E3 ligase activity of Keap1, so that Nrf2 escapes from the Keap1-mediated repression, migrates into the nucleus, and activates expression of its target genes. As oxidative stresses give rise to many diseases, Nrf2 inducers that interact with Keap1 cysteine residues or Keap1–Nrf2 binding surface are expected as drugs against these diseases. On the other hand, several lines of evidence have showed that cancer cells hijack the Keap1–Nrf2 system to obtain resistance of chemo- and radiotherapies. Somatic mutations in human KEAP1 and NRF2 genes are observed in a number of cancers, resulting in constitutive activation of NRF2 and poor prognosis. In this review, we describe molecular basis underlying the Keap1–Nrf2 function and drug discovery.