In lung cancer it is shown that mechanisms of the acquired resistance to receptor tyrosine kinase‐targeted therapy (TKI) involve secondary EGFR T790M mutation, MET amplification, activation of the mesenchymal‐epithelial transition factor/hepatocyte growth factor axis, induction of epithelial‐to‐mesenchymal transition, acquisition of stem cell properties, and transformation from NSCLC into small cell lung cancer, etc. Compensatory activation between central oncogenic pathways could be another key determinant of drug resistance as well as another target. This evidence concerns the gene HGF and lung cancer.