With the launch of the Constellation program, NASA finds itself with the opportunity to design the next generation of manned vehicles that will take man to the Moon and beyond in the next two decades. While there are precedents for many aspects of the design, development, test, and evaluation (DDT&E) task at hand - the Apollo program, Space Transportation System, International Space Station (ISS) and others - the Johnson Space Center (JSC) Astronaut Office asked for a fresh look at first principles during the formative times of this new program. As a result, a team directed by the NASA Engineering and Safety Center (NESC) collected methodologies for how best to develop safe and reliable human rated systems and how to identify the drivers that provide the basis for assessing safety and reliability. The team also identified techniques, methodologies, and best practices to assure that NASA can develop safe and reliable human rated systems. The results are drawn from a wide variety of resources, from experts involved with the space program since its inception to the best-practices espoused in contemporary engineering doctrine. This report focuses on safety and reliability considerations and does not duplicate or update any existing references. Neither does it intend to replace existing standards and policy.