Testing donations for pathogens and deferring selected blood donors have reduced the risk of transmission of known pathogens by transfusion to extremely low levels in most developed countries. Protecting the blood supply from emerging infectious threats remains a serious concern in the transfusion medicine community. Transfusion services can employ indirect measures such as surveillance, hemovigilance, and donor questioning (defense), protein-, or nucleic acid based direct testing (detection), or pathogen inactivation of blood products (destruction) as strategies to mitigate the risk of transmission-transmitted infection. In the North American context, emerging threats currently include dengue, chikungunya, and hepatitis E viruses, and Babesia protozoan parasites. The 2003 SARS and 2014 Ebola outbreaks illustrate the potential of epidemics unlikely to be transmitted by blood transfusion but disruptive to blood systems. Donor-free blood products such as ex vivo generated red blood cells offer a theoretical way to avoid transmission-transmitted infection risk, although biological, engineering, and manufacturing challenges must be overcome before this approach becomes practical. Similarly, next generation sequencing of all nucleic acid in a blood sample is currently possible but impractical for generalized screening. Pathogen inactivation systems are in use in different jurisdictions around the world, and are starting to gain regulatory approval in North America. Cost concerns make it likely that pathogen inactivation will be contemplated by blood operators through the lens of health economics and risk-based decision making, rather than in zero-risk paradigms previously embraced for transfusable products. Defense of the blood supply from infectious disease risk will continue to require innovative combinations of surveillance, detection, and pathogen avoidance or inactivation.