Smoking-related lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer are growing epidemics in women in the United States and elsewhere. Although some of this disturbing trend in women can be attributed to changing smoking habits, there is emerging evidence that women may be biologically more susceptible to the harmful effects of cigarette smoke than are men. Estrogen and related compounds may up-regulate the expression of cytochrome P450 (CYP) enzymes in lungs and liver, which are involved in the metabolism of various constituents of cigarette smoke. Although metabolism of foreign substances is usually beneficial in eliminating potential toxins from the body, in some instances the metabolic process can transform harmless substances into toxic chemicals through a process called metabolic bioactivation. One important xenobiotic substrate for CYP enzymes in cigarette smoke is polycyclic aromatic hydrocarbon, which in its native form is relatively harmless in small doses but upon bioactivation by CYP enzymes, can become very toxic substances for the lungs. In this article, we explore CYP and other related pathways as potential mechanisms and targets of future research and novel discoveries to curb the growing epidemic of COPD and lung cancer in women.