Patients with advanced-stage non-small-cell lung cancer (NSCLC) who harbour the EGFR T790M mutation often develop resistance to EGFR tyrosine-kinase inhibitors (TKIs), such as AZD9291. Now, an association study in patients who developed resistance to AZD9291 has identified three distinct mutations that all underlie resistance to this agent in patients with advanced-stage NSCLC and EGFR T790M mutations before commencing treatment. Analysis of plasma cell-free DNA samples from 15 patients with advanced-stage NSCLC who were resistant to AZD9291 revealed that six patients retained the T790M mutation and gained a further EGFR mutation (C797S), five patients retained the T790M mutation and a further four lost the T790M mutation but remained resistant to AZD9291. These findings indicate that the mutational landscape of patients with advanced-stage NSCLC is more complex than previously thought.