The comprehension of the mechanisms leading to the acquired resistance is complex due to different aspects such as: (1) the type of EGFR-TKI; (2) the line of treatment with a specific EGFR-TKI; (3) the tumour biology, in particular histology, intrinsic mutability, microenvironment, and the type of initial EGFR mutation. Here, EGFR is linked to neoplasm.