Premature birth is a significant global problem and the leading cause of newborn deaths. Tobacco smoking has been associated with premature birth for over 50 years. The mechanisms through which smoking exerts its effects on pregnancy outcomes remain unclear. In this review, we discuss rates of prematurity and smoking in pregnancy, the evidence of a causal relationship between tobacco and preterm birth, and proposed biochemical pathways through which the interaction is mediated. The suggested mechanisms include nicotine-induced vasoconstriction, carbon monoxide-induced fetal hypoxia, cadmium disruption of calcium signaling, altered steroid hormone production, disruption of prostaglandin synthesis, and changed responses to oxytocin. The relative importance of each of these pathways is yet to be ascertained. Further research is necessary to explore the mechanisms through which smoking exerts its effect on gestational length and the process of parturition. Moreover, the risks of nicotine replacement in pregnancy should be investigated further.