Trophoblast cell differentiation and fusion during human placentogenesis are controlled by a variety of regulatory genes and key molecules. In this review, we focus on the fusogenic protein syncytin, which originally derived from a human endogenous retrovirus and was discovered in 2000, and discuss its possible role in pre-eclampsia and HELLP syndrome. Secondly, we define a further regulator of placental syncytium formation, the transcription factor GCMa (or Gcm1, glial cells missing a). GCMa is the first transcription factor capable of initiating syncytiotrophoblast formation, and has been shown to activate syncytin gene expression as a possible underlying cell fusion event. GCMa is also thought to play a role in human placental diseases such as pre-eclampsia or intrauterine growth restriction (IUGR). Additionally, we discuss studies on the effects of hypoxia on trophoblastic cells. Since placental effectors stimulating cell differentiation also depend on local oxygen tension, oxygen availability or sensing, alterations of these conditions contribute to abnormal placental development. Pre-eclampsia is unique to human pregnancy, and its pathogenesis, certainly multifactorial, is still obscure. In conclusion, we propose that syncytin and GCMa are promising candidates for research into altered placenta formation and also for acquiring a basic knowledge of placental syncytialization processes.