Abstract: RAS, as a well-known proto-oncogene, is the most frequently mutated oncogene in human cancers, yet tremendous efforts over the past 30 years have failed to develop effective therapies for RAS-mutant cancer. Recently, specifically targeting the KRAS-G12C mutant, a frequently occurring KRAS mutation in human cancers, has shown promise in conquering KRAS-mutant cancers, and has inspired interest in this direction. We herein review the very recent progress achieved in the development of covalent inhibitors towards KRAS-G12C mutant, in combinational therapies and in proteolysis-targeting chimeras (PROTACs)-based approaches to disrupt KRAS-G12C protein. We provide insights for drug discovery against KRAS-G12C-mutated tumors and discuss the potential challenges in this field.