The RAS genes, which include H, N, and KRAS, comprise the most frequently 
mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C 
mutation - are found in most pancreatic, half of colorectal and a third of lung 
cancer cases and is thus responsible for a substantial proportion of cancer 
deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting 
efforts over the past 3-4 decades. These efforts have included targeting the 
KRAS protein itself but also its posttranslational modifications, membrane 
localization, protein-protein interactions and downstream signalling pathways. 
Most of these strategies have failed and no KRAS-specific drugs have yet been 
approved. However, for one specific mutation, KRASG12C , there is light on the 
horizon. MRTX849 was recently identified as a potent, selective and covalent 
KRASG12C inhibitor that possesses favourable drug-like properties. MRTX849 
selectively modifies the mutant cysteine residue in GDP-bound KRASG12C and 
inhibits GTP-loading and downstream KRAS-dependent signalling. The drug inhibits 
the in vivo growth of multiple KRASG12C -mutant cell line xenografts, causes 
tumour regression in patient-derived xenograft models and shows striking 
responses in combination with other agents. It has also produced objective 
responses in patients with mutant-specific lung and colorectal cancer. In this 
review, we discuss the history of RAS drug-targeting efforts, the discovery of 
MRTX849, and how this drug provides an exciting and long-awaited opportunity to 
selectively target mutant KRAS in patients.