Smoking remains a major health problem especially among women and it influences estrogen metabolism and the risk for multiple estrogen sensitive outcomes. Many indirect effects of smoking exist through the ability of the by-products to modify a variety of drugs, enzymes, and hormones. The results of several in vitro studies have shown that constituents of cigarette smoke have significant effects on production and metabolism of estrogens. In some cases, such as osteoporosis and endometrial cancer, smoking appears to attenuate the effects of estrogen. However, for other outcomes such as breast cancer, venous thromboembolic events (VTE), and coronary heart disease (CHD), the relationship between smoking and estrogen exposure is less defined. Based on the preponderance of evidence, smokers are likely to require higher doses of hormone replacement therapy (HRT) to achieve comparable clinical effect to that observed in nonsmokers. However, uptitrating the dose of HRT in smokers to achieve a desired systemic level or clinical response may simultaneously increase risk for adverse effects that are primarily driven by hepatic rather than systemic exposure. The healthy benefits from smoking cessation should be expressed to women who choose to use HRT, and every effort should be made to encourage them to stop smoking so that they can be effectively treated with the lowest possible dose of HRT.