More than 50 years after the discovery of RAS family proteins, which harbor the most common activating mutations in cancer, the U.S. Food and Drug Administration approved the first direct allele-specific inhibitor of mutant KRAS in lung cancer. We highlight the history of discovering RAS and decades of studies targeting KRAS-driven lung cancer. A landmark article by Shokat and colleagues in 2013 elucidated allosteric inhibition of this undruggable target and paved the way for the first-in-class direct KRASG12C inhibitor. Although these drugs have impressive 36%-45% objective response rates with a median duration of response of 10 months, many tumors do not respond, and diverse mechanisms of resistance have already been observed; this includes new KRAS alterations, activation of alternate RTK pathway proteins, bypass pathways, and transcriptional remodeling. These resistance mechanisms can be profiled using tissue-based and plasma-based testing and help to inform clinical trial options for patients. We conclude with a discussion of research informing ongoing clinical trials to rationally test promising treatments to thwart or overcome resistance to KRASG12C inhibitors and target other KRAS-altered lung cancers.