Lung cancer is the leading cause of death from neoplasia in men and women in the United States. Some studies suggest that women are more susceptible than men to tobacco-induced carcinogenesis and may show higher risk than men for lung cancer development from smoking. More recently, increasing biochemical and genetic data have supported this male-female difference in response to tobacco. Estrogens may be involved in lung carcinogenesis, and estrogen receptors (ERs), mainly ERb, are present and functional in normal lung and tumor cell lines and tissues. Estrogen can directly stimulate the transcription of estrogen-responsive genes in the nucleus of lung cells, and it can also transactivate growth factor signaling pathways, in particular the epidermal growth factor pathway. Lung cancer patients currently have few effective therapeutic options. An understanding of these new developments in estrogen signaling and cross-talk pathways may pave the way for innovative combinatorial approaches for treatment of lung cancer and possibly chemoprevention.