Besides epidermal growth factor receptor (EGFR) gene mutations, clinical factors such as smoking status have been identified as predictors for survival for NSCLC patients treated with EGFR-tyrosine kinase inhibitors (TKI). However, the biological screening for EGFR gene mutations is not routinely available everywhere. Therefore, the question arises if the decision to treat patients with EGFR-TKI should be based on clinical factors, and in particular smoking status, alone. We illustrate the difficulties faced by clinicians with the case of a 56-year-old man with stage IV lung adenocarcinoma and a smoking history of 30-pack-year. This patient received erlotinib first-line after its enrolment in a clinical trial. After 4 months, he presented with a dramatic clinical and radiological response. The biological analysis of the tumour revealed an EGFR exon 19 deletion. This report emphasizes that smoking status alone appears inappropriate in selecting patients for EGFR-TKI treatment. In addition, the relatively high number of (ex-)smokers retrieved from prospective studies on NSCLC patients with tumours showing an EGFR mutation should be emphasized, as it represents up to 30% of patients. Therefore, a biological rather than a clinical selection for patients' eligibility for EGFR-TKI appears mandatory.