Oral hypoglycemics have been avoided in pregnancy due to their potential to cause fetal hyperinsulinemia/hypoglycemia. A recent human study has shown glyburide to minimally cross the placenta, allowing a safe new treatment for gestational diabetes. The mechanisms for the minimal placental passage of this small molecule are not clear. In this presentation, the role of pKa, molecular weight, lipid solubility, and protein binding is considered. Out of these physical and pharmacologic characteristics, the very extensive plasma protein binding and short elimination half-life of glyburide appear to be major determinants of its minimal transplacental transfer.