This important study by Tsai and colleagues illuminates the multifaceted mechanisms of acquired resistance to direct inhibition of KRAS G12C, including the reactivation of KRAS-mediated signaling, YAP signaling, the activation of EMT, metabolic reprogramming, and diverse changes in the tumor microenvironment (TME), including coagulation, angiogenesis, and immune escape pathways (ref. 9 and Figure 1). The gene discussed is KRAS; the disease is neoplasm.