Each year more than 400,000 Americans die from diseases directly related to smoking, and lung cancer is now the leading cause of death from neoplasia in U.S. men and women. Cancer of the lung and bronchus was responsible for one-quarter of all cancer deaths among U.S. women last year, killing approximately 67,000 women. This is related both to the demographics of smoking among women and the poor survival rate for persons with lung cancer. Epidemiologic evidence from a number of studies suggests that women are more susceptible to tobacco-induced carcinogenesis than men, taking into account baseline exposure, body weight, body height, and body mass index. More recently, there has been increasing biochemical and genetic data to support this male-female difference in susceptibility. Patients with lung cancer currently have few therapeutic options. Understanding these new genetic developments may pave the road for innovative therapeutic approaches for women and new screening methods to determine those at greatest risk for developing lung cancer. Clearly, smoking-related disease among women is a major public health issue that will require effective programs for smoking prevention and cessation among females. Both sex and gender differences in smoking-related disease will be discussed in this review.