A significant fraction of drugs fail during or after clinical trials due to safety and efficacy. Such failure demonstrates the limitations of preclinical testing. Advances in tissue engineering, microfluidics and methods to culture primary and induced pluripotent stem cells of human origins provides new opportunities to develop in vitro systems to test and screen drugs. NIH and DARPA have taken a lead role to foster the development of microphysiological systems that involve the use of human cells and that predict drug effectiveness, toxicity, and key pharmacodynamics properties. Key requirements for systems design involve developing tissue or tissue mimics that represent the structure and function of key organ functions, replicating key system dynamics, scaling the relationships among organs and body fluid, monitoring key functions, developing a common culture media and modeling system performance. Our team is developing a circulatory system that consists of a high-pressure small diameter arterial system interfaced with three-dimensional skeletal muscle. We’re the first group to show key muscle and blood vessel functional responses with engineered organ systems using human cells. Additional progress in addressing the key challenges in our system will be presented.