Cigarette smoking adversely affects every organ system. Paradoxically, smoking during pregnancy has been associated with a reduced risk of preeclampsia. We reviewed previous epidemiologic and clinical studies on the association between smoking and preeclampsia from 1959 to March, 2006. A total of 48 epidemiologic studies were identified. Overall, smoking during pregnancy reduces the risk of preeclampsia by up to 50% with a dose-response pattern. A protective effect was consistently found in both nulliparas and multiparas, singleton and multifetal pregnancies, and for mild and severe preeclampsia. Evidence on whether quitting smoking before or in early pregnancy reduces the risk remains inconclusive. To understand possible biologic mechanism(s) of the protective effect, we reviewed literature on potential pathophysiology of smoking and its effects on placenta, cardiovascular and immune systems. Although current literature does not lend clear evidence to support a particular mechanism for the protective effect of smoking, smoking might have effects on angiogenic factors, endothelial function and the immune system which act to lower risk of preeclampsia. More epidemiologic studies with biochemically confirmed smoking status and laboratory studies with a focus on promising pathways are warranted to further clarify this puzzling relationship. Understanding the underlying mechanisms through which smoking reduces preeclampsia risk may enhance our understanding of the pathogenesis of this disorder and contribute to the development of prevention strategies.