The epidermal growth factor receptor (EGFR) and its ligands are frequently expressed in non-small-cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib have shown clinical activity in NSCLC. However, only a small subgroup of NSCLC patients respond to these agents, suggesting that patients selection is critical for EGFR TKIs sensitivity. In this regard, several studies have tried to individuate prognostic and predictive factors that are associated with sensitivity or resistance to anti-EGFR agents. A strong correlation between activating mutations in the EGFR TK domain and response to erlotinib and gefitinib has been reported in different trials. However, patients without EGFR mutations might also benefit of treatment with these drugs by experiencing prolonged disease stabilization. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding the association between EGFR gene amplification and clinical response to TKIs. Different mechanisms of resistance to EGFR TKIs have also been described. Mutations of KRAS, that occur in approximately 20% of NSCLC, are associated with reduced response to EGFR TKIs. The EGFR T790M mutation, that reduces the affinity of the EGFR to gefitinib and erlotinib, and MET gene amplification produce acquired resistance to anti-EGFR agents. Taken together, these findings suggest that several different molecular alterations regulate the sensitivity of NSCLC cells to EGFR TKIs, and that a comprehensive approach to this phenomenon is necessary for an appropriate selection of patients that should be treated with these drugs.