Abstract Initial studies with the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib in patients with non-small cell lung cancer (NSCLC) showed that, although most did not have an objective radiographic response, a minority of patients had dramatic and durable clinical and radiographic responses. The discovery of EGFR mutations in tumours from patients with NSCLC and the association of these mutations with clinical response to gefitinib and erlotinib provided an opportunity to tailor treatment to the mutation profile of the tumour. A number of retrospective reviews and prospective trials have established that gefitinib or erlotinib therapy leads to radiographic responses in ∼75–80% of patients with NSCLC with EGFR mutations. Although a variety of mutations in EGFR have been identified, the two most common somatic activating EGFR mutations are the LREA deletions in exon 19 and the L858R substitution in exon 21. Together, these mutations make up 85–90% of EGFR mutations. At least two retrospective reviews have indicated a difference in the outcome of patients with different EGFR mutations: after treatment with gefitinib or erlotinib, patients with exon 19 deletions have an increased survival compared with those patients whose tumours have an L858R substitution. These findings remain to be confirmed in prospective studies. Improved understanding of the association of EGFR mutations with clinical outcome may improve the ability of physicians to match treatment to mutation status for patients with NSCLC.