Since the 1960s man has searched for ways to establish a human presence in space. Unfortunately,, the development and operation of human spaceflight vehicles carry significant safety risks that are not always well understood. As a result, the countries with human space programs have felt the pain of loss of lives in the attempt to develop human space travel systems. Integrated System Safety is a process developed through years of experience (since before Apollo and Soyuz) as a way to assess risks involved in space travel and prevent such losses. The intent of Integrated System Safety is to take a look at an entire program and put together all the pieces in such a way that the risks can be identified, understood and dispositioned by program management. This process has many inherent challenges and they need to be explored, understood and addressed. In order to prepare truly integrated analysis safety professionals must gain a level of technical understanding of all of the project's pieces and how they interact. Next, they must find a way to present the analysis so the customer can understand the risks and make decisions about managing them. However, every organization in a large-scale project can have different ideas about what is or is not a hazard, what is or is not an appropriate hazard control, and what is or is not adequate hazard control verification. NASA provides some direction on these topics, but interpretations of those instructions can vary widely. Even more challenging is the fact that every individual/organization involved in a project has different levels of risk tolerance. When the discrete hazard controls of the contracts and agreements cannot be met, additional risk must be accepted. However, when one has left the arena of compliance with the known rules, there can be no longer be specific ground rules on which to base a decision as to what is acceptable and what is not. The integrator must find common grounds between all parties to achieve concurrence on these non-compliant conditions Another area of challenge lies in determining the credibility of a proposed hazard. For example, NASA's definition of a credible hazard is accurate but does not provide specific guidance about contractors declaring a hazard "not credible" and ceasing working on that item. Unfortunately, this has the side effect of taking valuable resources from high-risk areas and using them to investigate whether these extremely low risk items have the potential to become worse than they appear. In order to deal with these types of issues, there must exist the concept of a "Safe State" and it must be used as a building block to help address many of the technical and social challenges in working safety and risk management. This "Safe State" must serve as the foundation for building the cultural modifications needed to assure that safety issues are properly identified, heard, and dispositioned by our space program management. As the space program and the countries involved in it move forward in development of human rated spacecraft, they must learn from the recent Columbia accident and establish new/modified basis for safety risk decisions. Those involved must also become more cognizant of the diversity in safety approaches and agree on how to deal with them. Most of all, those involved must never forget that while the System Safety duty may be difficult, their efforts help to preserve the lives of space crews and their families.