We report the case of a Caucasian female never smoker with erlotinib sensitive metastatic non-small cell lung cancer in the brain. Having progressed after receiving whole brain radiotherapy, her brain metastases responded both initially and on re-treatment with erlotinib. However, her extra-cranial disease remained erlotinib-resistant throughout. This case demonstrates that brain metastases may be sensitive to erlotinib and also highlights the oligoclonal nature of non-small cell lung cancer reflected by differential tyrosine kinase inhibitor tumour sensitivity. On the basis of this case we suggest that erlotinib should be considered in the treatment paradigm for patients with intra-cranial disease and propose further study into the continued use of this drug in the situation where there is a differential response.