Endothelial cells play a vital role in the human vascular system. Injury to this layer of cells can lead to devastating consequences and eventually mortality. As demonstrated by recent accumulating evidences, the injured endothelial layer can be rescued by endothelial cell-based therapy. However, the limited source of functional endothelial cells which can be used in clinical surgery, is hugely hampered. The discovery of pluripotent embryonic stem cells, nevertheless has raised hope for generating endothelial cells in the regenerative medicine field. It was demonstrated that the concerted and coordinated series of specific signaling pathways involving different molecules, guide the differentiation of these embryonic stem cells into functional endothelial cells. Moreover, it is believed that understanding the molecular mechanisms of endothelial development and signal pathways leading to endothelial differentiation from stem cells, will be essential for potential cell therapy for vascular disease. This review therefore, will summarize and discuss recent insights into endothelial development and the signaling pathways regulating embryonic stem cell differentiation towards the endothelial lineage.