Until the last decade, oral hypoglycemic agents have not been recommended in pregnancy owing to fear of their potential adverse fetal effects, including teratogenicity and neonatal hypoglycemia. However, the evidence in support of these recommendations is weak and is principally based on case series involving the use of first-generation sulfonylureas. Studies using a single-cotyledon placental model have found glyburide to only minimally cross the placenta, an observation that paved the way for a landmark randomized clinical trial that found glyburide to be as safe and effective as insulin in the management of gestational diabetes mellitus. Still, contradicting results regarding its trans-placental transfer, lack of adequate data regarding its safety during the first trimester and reports of increased neonatal morbidity raise concerns regarding the universal application of glyburide as an alternative to insulin therapy in diabetic pregnant women. Thus, there is a need for large, randomized, controlled trials with adequate power to evaluate the possibility of increased neonatal metabolic complications as well as the long-term outcome of infants born to mothers treated with glyburide and insulin. Unless future studies refute current data regarding the efficacy and safety of glyburide, we believe that, owing to its ease of administration, convenience and low cost, glyburide will become the first line of medical treatment in patients with gestational diabetes mellitus within the next few years.