Across a broad range of human cancers, gain-of-function mutations in RAS genes 
(HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible 
for tumorigenesis and cancer progression. The targeting of RAS with drugs is 
challenging because RAS lacks classic and tractable drug binding sites. Over the 
past 30 years, this perception has led to the pursuit of indirect routes for 
targeting RAS expression, processing, upstream regulators, or downstream 
effectors. After the discovery that the KRAS-G12C variant contains a druggable 
pocket below the switch-II loop region, it has become possible to design 
irreversible covalent inhibitors for the variant with improved potency, 
selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and 
adagrasib (MRTX849), were recently evaluated in phase I-III trials for the 
treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a 
new era of precision oncology. In this review, we outline the mutations and 
functions of KRAS in human tumors and then analyze indirect and direct 
approaches to shut down the oncogenic KRAS network. Specifically, we discuss the 
mechanistic principles, clinical features, and strategies for overcoming primary 
or secondary resistance to KRAS-G12C blockade.