Pre-eclampsia is a hypertensive disorder of pregnancy characterized by shallow placentation, inadequate placental perfusion, localized placental oxidative stress, a heightened maternal inflammatory response and subsequent maternal endothelial dysfunction. This pathophysiology leads to an increase in maternal blood pressure, edema and proteinurea. Interestingly, women who smoke cigarettes throughout pregnancy are at a 33% reduced risk of developing this disorder. The exact mechanisms through which cigarette smoke reduces the risk of pre-eclampsia are not yet understood. We propose that cigarette smoke reduces the risk of developing pre-eclampsia via direct placental effects. In this review we will address, and provide evidence for, our specific hypotheses that: (a) CO increases trophoblast invasion and spiral arteriole remodeling; (b) CO decreases a localized inflammatory response at the level of the decidua; (c) CO increases utero-placental, intra-placental and feto-placental blood flow; (d) CO decreases hypoxia-induced apoptosis of the syncitiotrophoblast layer; (e) CO activates hemoproteins involved in normal endothelial functioning normally acted upon by NO; (f) compound(s) within cigarette smoke result in upregulation of antioxidant systems within the placenta. These various mechanisms of action must be further examined as they may provide valuable keys to novel therapeutic design in the realm of pre-eclampsia research.