In humans, the placenta that forms by an implantation process in the maternal uterus allows the development of the embryo and the fetus by exchanging ions, metabolites, and wastes and by producing specific hormones (steroids and proteins) with the levels of secretion often surpassing the levels of other endocrine organs. The process of placental development involves two pathways of differentiation that lead to the formation of two distinct phenotypes: villous trophoblast (fusion phenotype) and extravillous trophoblast (proliferative/invasive phenotype). In this chapter we describe the current methods to study villous trophoblast differentiation and the cell–cell fusion of the cytotrophoblast cells.