The recent success of KRas G12C irreversible inhibitors has bolstered our ability to manage KRas mutant disease significantly, but these drugs are insufficient on their own. Targeted chemical inhibition is a viable therapeutic strategy but one with an inherent risk for the development of resistance mechanisms. Data from the clinical trials for two such inhibitors, sotorasib (Amgen) and adagrasib (Mirati), have confirmed that resistance mechanisms will impede the efficacy of these drugs and cap the durability of response to the short term. In the clinical trial for the management of lung cancers with sotorasib, an objective response was observed in 37% of patients, and the median duration of response was 11 months. While this level of efficacy is still an appreciable benefit to the management of advanced lung cancer, it also indicates that both innate and acquired resistance to the inhibitor monotherapy are present. In a recent study of patients enrolled in the adagrasib clinical trial, a variety of resistance mechanisms were discovered and characterized. Most commonly, compensatory mutations that allowed reamplification of RTK/MAPK/PI3K pathways were observed, including additional mutations to KRas genes. This study confirms that resistance to KRas G12C inhibition can occur in a variety of ways and will likely occur in patients treated with these inhibitors given sufficient time. Despite these inherent challenges, the KRas G12C irreversible inhibitors still represent a significant scientific breakthrough and will be of great benefit to patients. Rather than developing additional orthogonal treatments for KRas G12C mutant cancers, developing means to extend the viability and lifetime of these existing drugs is an attractive approach.