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ABSTRACT Introduction KRAS G12C targeted covalent inhibitors for cancer therapy are revolutionary. However, resistance to KRAS G12C inhibitors in clinical trials is a proven fact. Areas covered The authors focus on providing coverage and emphasizing the strategy of conquering KRAS G12C inhibitor resistance from the perspective of clinical therapy. The authors also provide the readers with their expert perspectives for future development. Expert opinion It is essential to improve the therapeutic effect and achieve long-term disease control through accumulating rapid exploration of drug resistance mechanisms in preclinical trials and developing rational combination dosing approaches from clinical practice. Our presentation of the perspective provides insights into drug resistance in this groundbreaking area of research.