Trophoblast giant cells (TGCs) are the first cell type to terminally differentiate during embryogenesis and are of vital importance for implantation and modulation of post-implantation placentation. TGCs are mononuclear and polyploid but are heterogenous and dynamic. At least four different subtypes of TGCs are present within the mature placenta that have distinct cell lineage origins. The development of TGCs is complex and requires transition from the mitotic to the endoreduplication cell cycle and is regulated by a wide variety of factors. During early gestation, TGCs mediate blastocyst attachment and invasion into the uterine epithelium, regulate uterus decidualization, and anatomosis with maternal blood spaces to form the transient yolk sac placenta. During later gestation, TGCs secrete a wide array of hormones and paracrine factors, including steroid hormones and Prolactin-related cytokines, to target the maternal physiological systems for proper maternal adaptations to pregnancy and the fetal-maternal interface to ensure vasculature remodeling. The large number of mouse mutants with defects in TGC development and function are giving us significant new insights into the biology of these fascinating cells.