Kelch-like ECH associated protein 1(Keap1), a typical substrate-recognition subunit of the Cul-RING E3 ligase, plays a significant role in ubiquitination. Ubiquitination, an important post-translational modification, enables a degradation signal in both autophagy and ubiquitin-proteasome system. Recently, several substrates can be recognized and binded by wild-type Keap1, and subsequently degraded by ubiquitin proteasome system (UPS) via Keap1-Cul3-Rbx1 complex. Additionally, Keap1 has also been widely studied as a tumor suppressor protein, and mutation or abnormally deletion of Keap1 alleles contributes to different kinds of diseases. The study of Keap1 has mainly concentrated on the Keap1-Nrf2 axis, but rarely extends to downstream substrates. Given that the great importance of Keap1 in cells, this review summarizes the current research status of Keap1, including ubiquitin-proteasome system, Keap1’s structure and function, the mutation of Keap1, the substrates of Keap1, and Keap1-related diseases. It may provide a new thought for targeted therapy of Keap1-associated diseases through discussing the challenges of Keap1-related fields in clinic.