The use of indomethacin as a tocolytic agent in patients with premature labor was first reported by Zuckerman in 1974. Since then, prostaglandin synthetase inhibitors (PSI) have been used in pregnancy for a variety of indications. However, serious fetal side effects of this category of drugs continue to be reported. We present a review of the literature and the experience at our institution on the use of indomethacin, the most commonly prescribed antiprostaglandin in pregnancy. Therapeutic guidelines and surveillance recommendations for the use of PSI in pregnancy are proposed. The role of newer PSI in pregnancy and their side effect profile are also presented.