Stem cells, including embryonic stem cells (ESC) and induced pluripotent stem (iPS) cells, have been speculated as tools for studying development as well as prospective sources for tissue engineering. However, a major challenge in building tissues and organs is the lack of a vascular system. The development of the vascular system in vivo, starts with ESC differentiating into vascular progenitor cells (VPC), which further differentiates into endothelial cells (EC) and smooth muscle cells (SMC). Studying EC differentiation and the synergistic effects of molecular, cellular, and physical cues that drive blood vessel formation can provide researchers with the means to develop larger tissues in vitro, as well as therapies against vascular diseases in adults. The guidance of stem cell differentiation has largely relied on biochemical factors, but the precise combinatorial signals in the vascular niche has yet to be defined. In this study, mechanical signaling and patterning was explored by probing various components in the microenvironment. Specifically, I 1) studied stiffness directed vascular differentiation, 2) generated vascular patterns with use of biomimicry; 3) optimized human stem cell EC differentiation to form vascular networks.