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Abstract Adeno‐to‐squamous transition (AST) has emerged as a driver of targeted therapy resistance. Studies of KRAS/LKB1‐mutant non‐small cell lung cancer (NSCLC) have revealed the progressive acquisition of squamous signatures during treatment with KRAS inhibitors, ultimately inducing drug resistance. Moreover, the expression of squamous‐related gene KRT6A in adenocarcinoma (ADC) correlates with poor responses to KRAS inhibitors. In this commentary, we discuss the role of AST in drug resistance and propose future directions to elucidate the underlying mechanisms. Key points Adeno‐to‐squamous transition (AST) drives targeted therapy resistance. Progressive plasticity is acquired during Adeno‐to‐squamous transition (AST).