Formal processes to assess risk are well established in numerous areas of society including the environment, transportation, energy and food production sectors as well as some areas of health care such as new drugs or other therapeutic goods. However, these processes and their associated frameworks have only recently come to be used to make decisions in blood transfusion practice or in blood system policy development. This review describes the evolution of the use of risk-based decision making and discusses the elements that should be considered in its application to blood system issues. Following the identification and characterization of the risk, a structured process is undertaken to assess the magnitude of the risk and the level of risk reduction that can reasonably be achieved in the context of the complexity of the risk management action proposed and its cost. Inputs must be sought from appropriate subject matter experts, but also from those who can consider issues of ethics and social values. Engagement of the public is an essential step. Proposed interventions should be assessed for their likelihood of mitigating the risk and the proportional resource allocation in comparison with similar risks to the blood system or health system. Examples are provided of how a risk-based decision-making framework is used to address identified risks in the blood system.