||Syncytin-1 and Syncytin-2 are two human endogenous retroviral glycoproteins that are expressed in the human placenta. In this tissue, both proteins play important roles in the development of a healthy and functional placenta. Indeed, the conserved fusogenic properties that characterize Syncytin proteins among the mammalian clade are believed to be crucial for the formation of the syncytiotrophoblast (STB) layer of the placenta. Moreover, human Syncytins harbor functional immunosuppressive domains, which could be implicated in the regulation of the maternal immune system during pregnancy. Similar results have been described for the equivalent murine Syncytin-A and -B in terms of their essential placental function. Furthermore, the biological function of Syncytin-1 and -2 might be linked through their presence on the surface of small extracellular vesicles, including exosomes. As important proteins for the development of the placenta, dysregulation of Syncytin-1 and -2 expression is linked to different pathologies, such as preeclampsia and HELLP syndrome. Human Syncytins are also associated to other diseases. Hence, the abnormal expression of these placenta-specific fusogenic proteins in other tissues has been linked to several different types of cancers. As Syncytin-1 and -2 are associated to exosomes, their levels could be monitored through analyses of blood-derived exosomes and thereby be used for early diagnosis of placental disorder or potentially monitoring the progression or aggressiveness of various cancers.