Interest for development of molecular biomarkers tends to increase in clinical management of lung cancer. Indeed implementation in clinics of new molecules targeting epithelial growth factor (EGFR) such as erlotinib or gefitinib, rise several questions regarding the potential value of EGFR and KRAS mutations to predict therapeutic response. In the current review, we discuss the utilization of such biomarkers regarding published clinical data and the possibilities versus limitations associated with analyses performed in molecular laboratory on a daily setting basis.