Vascular differentiation and formation (morphogenesis) takes place in an intricate milieu. This unique microenvironment is situated throughout the body in diverse types of healthy tissues, yet it seems to activates/inhibits similar mechanisms of the microvasculature. Two parameters of this microenvironment seem critical for blood vessel growth and stabilization: (i) the extracellular matrix, which provides critical support for vascular cell adhesion, proliferation, migration, and morphogenesis, and (ii) low oxygen concentrations (hypoxia), which is a critical factor promoting vascularization during embryonic development and tumor growth. In this talk I will present our recent efforts to understand how these physicochemical cues and downstream signaling pathways impact vascular fate and assembly from progenitors and pluripotent stem cells.