Targeted therapy against epidermal growth factor receptor (EGFR) in non-small-cell lung cancer has heralded an era of mutationally targeted inhibition of this receptor and its oncogenic signal transduction using the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. EGFR TKIs have helped facilitate the concept of "personalized" cancer therapy into a reality. A majority of unselected patients remain as nonresponders with primary resistance to EGFR TKIs. Initial responders to EGFR TKIs all invariably relapse later with resistant disease. The optimal alternative therapeutic approach after a failed therapeutic trial of treatment with EGFR TKI remains to be better defined. Herein, we report a case of a patient with recurrent metastatic lung adenocarcinoma-bronchioloalveolar carcinoma that showed primary insensitivity to erlotinib therapy who later demonstrated substantial durable response to single-agent pemetrexed. We also present discussion on the evolving paradigm of the use of erlotinib in lung cancer and the current status of determinants of sensitivity in pemetrexed chemotherapy.