This article focuses on a systems biology approach to studying the pathophysiology of cigarette smoking during pregnancy. Particular emphasis is given to the damaging role of oxidative stress. Cigarette smoking exerts multiple adverse affects but abundant evidence, mostly in adults, suggests that oxidative stress and free radical damage is a major pathophysiological factor. Smoking during pregnancy is known to contribute to numerous poor birth outcomes, such as low birth weight, preterm birth as well as life-long health and developmental problems. It is clinically important to know the separate contributions that cigarette derived-nicotine and smoking-induced free oxidative stress make to these poor outcomes. Surprisingly, the extent to which smoking dependent oxidative stress contributes to these poor outcomes is not well studied but the application of redox proteomics should be useful. Considerable biochemical evidence suggests that antioxidants, such as tocopherols and ascorbate, could be useful in minimizing oxidative stress induced pathology to the developing fetus in those women who, despite medical advice, continue to smoke. Nevertheless, this suggestion has yet to be tested in well-designed clinical studies.