Inhibition of the epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC) is an exciting and rapidly evolving field. Erlotinib and gefitinib, two tyrosine kinase inhibitors (TKIs) of EGFR, have demonstrated activity in advanced NSCLC in the second- and third-line settings. Subset analyses of phase II and phase III clinical trials lead to the recognition that these two agents had more activity in certain subsets of NSCLC patients including never smokers, people of Asian descent and patients with EGFR FISH-positive or mutation-positive tumors. In particular, never smokers had statistically significant improvements in survival with either erlotinib or gefitinib therapy. Patients with EGFR FISH- or mutation-positive tumors had improved response rates to TKI therapy while those with KRAS mutant tumors did not derive any benefit. In the BR.21 trial treatment with erlotinib resulted in statistically significant improvements in overall survival and quality of life. Thus, while the question of who should receive EGFR TKI therapy is still not completely answered, all patients should be considered for erlotinib therapy in the second- or third-line setting. In daily clinical practice, there is currently no data to support the use of EGFR mutation or FISH status in this decision making process. Prospective trials are ongoing to determine which patient and tumor characteristics are predictive of a clinical benefit from TKI therapy.