The placenta sustains the developing fetus throughout gestation and its major functions include nutrition, gas and waste exchange via a variety of passive or active mechanisms. Up to 30 g of calcium (Ca(2+)) actively crosses the trophoblast layer during human pregnancy. The Ca(2+) ion not only plays an important role for skeletal development but is also an essential second messenger. This review is intended to highlight the implications of Ca(2+) signaling during reproduction and specifically placentation. Initially, a Ca(2+) wave induces fertilization of the oocyte. The intracellular Ca(2+) concentration is key for the blastocyst implantation, proper placental development and function. Current knowledge of many proteins involved in placental Ca(2+) regulation and their function in pathologic conditions is largely limited. Recent studies, however, point to alterations in Ca(2+) homeostasis in placental pathologies such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR). A broader understanding of the role of Ca(2+) signaling during human reproduction may offer insight into impaired pregnancy outcomes.