Development of blood vessels takes place via two subsequent processes, vasculogenesis and angiogenesis. During vasculogenesis, formation of first blood vessels is achieved by differentiation of hemangiogenic stem cells from pluripotent mesenchymal cells, while during angiogenesis new blood vessels form from already existing vessels. The combination of our data with those from the literature leads us to depict the chronological steps of cell differentiation in the mesenchymal core of placental villi during vasculogenesis and angiogenesis. This current opinion will focus on the temporal and spatial expression of VEGF and its receptors VEGFR-1 and VEGFR-2, and the angiopoietin receptors Tie-1 and Tie-2 in parallel to vascular maturation in human placental villi during very early stages of placental development. There is evidence that the interplay of a variety of growth factors secreted from different cell types during development is needed to trigger as well as maintain placental vasculogenesis and angiogenesis.