The discovery of several clinically relevant resistance mechanisms to targeted cancer drugs, for example mutations affecting FLT3N676 or FLT3G697 in acute myeloid leukemia [23–25], amplification of the MET gene in EGFR mutant lung adenocarcinoma [13] or BRAFV600E splice variants in melanoma [26], was achieved through systematic analysis of in vitro cancer models with experimentally induced insensitivity to the respective agents. The gene discussed is EGFR; the disease is lung adenocarcinoma.