The US blood safety vigilance system is composed of a network of interwoven programs, now organized under a formal structure, with the Assistant Secretary of Health and DHHS Blood Safety Committee bearing overall responsibility. It takes advantage of the breadth of expertise and close collaborative relationship of transfusion medicine and infectious disease scientists within and outside of the government. Core elements include an array of ongoing surveillance programs for monitoring established as well as new and emerging infectious agents that may pose a risk to blood safety, and the existence of historical and contemporary repositories of donor and recipient specimens that enable rapid investigation of putative new risks. This report summarizes the historical events that shaped the US blood safety oversight system, reviews the current organization and decision-making processes related to blood safety issues, and highlights key surveillance systems and research programs which monitor the US and global blood supplies for known and potential emerging risks.