EMP-1 is identified as a surface biomarker whose expression correlates with acquisition of gefitinib resistance. EMP-1 expression is further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance is independent of gefitinib-sensitizing EGFR somatic mutations.