ZD1839 ('Iressa') is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that inhibits EGFR signaling. Emerging evidence indicates that ZD1839 has clinical potential in lung cancer, but very little is known about the molecular characteristics of lung cancers that may determine sensitivity to ZD1839. We examined a panel of 19 lung cancer cell lines to investigate possible association between ZD1839 sensitivity and histological type, expression level and constitutive phosphorylation of EGFR and K-ras gene status. Our results indicate that neither expression level nor constitutive activation status of EGFR seems to predict sensitivity to ZD1839. In addition, ZD1839 sensitivity was not associated with expression of human epidermal growth factor receptor-2 (HER-2), another member of this tyrosine kinase receptor family nor with co-expression of EGFR and HER-2. Finally, no correlation was found between the presence of activating mutations of the K-ras gene, an important downstream mediator of the EGFR-transduced signals and the relative resistance to ZD1839. These findings warrant future study to clarify how ZD1839 inhibits lung cancer cell growth and to find a useful marker for prediction of sensitivity to this novel and promising agent for the treatment of lung cancers.