Designing and manufacturing of vascular prosthesis for arterial bypass grafts is a very complex problem. The process involves the selection of suitable geometry, materials of appropriate characteristics, and manufacturing technique capable of constructing prosthesis in a cost-effective manner. In this chapter, all engineering aspects related to the design and optimization of an artificial graft are presented and discussed. These aspects include CAD design of the graft, in vitro hemodynamic analysis to ensure good mechanical integrity and functionality, and optimization of the manufacturing techniques. Brief discussion is also given on the endothelization and vascularization of the artificial vessels and the future directions of the development of synthetic vessels for human implementation.