Lung cancer is the leading cause of cancer deaths in the United States. Over 80,000 new lung cancers were diagnosed in United States among women in 2004, and 68,500 of those women will die from the disease. Interestingly, lung cancer appears to be a biologically different disease in women. We recently identified a new class of genetic mutations in lung cancer in a gene called the epidermal growth factor receptor (EGFR). Strikingly, the mutations are significantly more common in women (20%) than men (9%). This observation raises the possibility that interactions between EGFR and estrogen might be important in the development of tumors harboring EGFR mutations. Based on preliminary observations, we speculate that estrogen antagonizes EGFR function in lung cancer, and we hypothesize that relatively high levels of estrogen normally prevent the development of tumors harboring EGFR genetic alterations. As a consequence, tumors harboring EGFR mutations arise when estrogen levels decrease. The observation that EGFR mutations occur at higher frequency in post-menopausal women, in which estrogen levels drop to concentrations even lower than in men of similar age, supports this hypothesis. We propose studies to directly test this interesting possibility.