During human placentation, mononuclear cytotrophoblasts fuse to form a multinucleated syncytia ensuring hormonal production and nutrient exchanges between the maternal and fetal circulation. Syncytia formation is essential for the maintenance of pregnancy and for fetal growth. The trophoblast cell fusion process first requires the acquisition of cell fusion properties, then cells set up plasma membrane protein macrocomplexes and fusogen machinery that trigger cellecell fusion. Numerous proteins have been shown to be directly involved in the initiation of trophoblast cell fusion. These proteins must expressed at the right time and in the right place to trigger cellecell fusion. In this review, we describe the role of certain fusogenic protein macrocomplexes that form the scaffold for the fusogen machinery underlying human trophoblastic-lipid mixing and merging of cell contents that lead to cell fusion in physiological conditions.