Placenta forms a vital link between the mother and fetus. It is responsible for transferring of nutrients and gases from mother to the fetus, removal of wastes from the fetus, safeguards the fetus by filtering toxic and immunogenic substances, it synthesizes hormones, few proteins and it also causes metabolic alteration of maternal nutrients for the fetus. Placenta is a dynamic organ and undergoes changes throughout pregnancy. As the gestational age advances, there are specific periods of placental development which are modified due to metabolic insults caused by pregestational or gestational diabetes. During first trimester, pregestational diabetes modifies trophoblastic invasion, placental anchoring, uterine vascular remodeling, and vascular development. This chapter covers the effect of maternal diabetic environment, effects of fetal hyperinsulinemia, placental cytokines, and antidiabetic agents and placenta. The human placenta synthesizes a variety of cytokines which regulate insulin action in response to hyperglycemia. It includes tumor necrosis factor (TNF), leptin, and interleukin-6 (IL-6).