Infectious diseases pose a major threat to safety of blood transfusion, organ and tissue and cell-based immunotherapies. Blood services worldwide perform very large-scale screening of blood donors for the major transfusion-transmissible infections (TTIs), HIV-1, hepatitis B and C viruses. However, ongoing and rapidly evolving threats to blood and transplant safety include the currently expanding number or arthropod-borne viruses, such as the current rapid northward expansion of West Nile, Chikungunya and Dengue viruses in Europe, and outbreaks of Oropouche and Zika viruses in Central and South America. The impact on blood and transplant safety of human virome components, including the large number of recently described and often highly prevalent human polyomaviruses, parvoviruses, papillomaviruses and anelloviruses, and human herpesviruses (HHVs) such as HHV-6 and − 7, remains poorly understood. Advances in genomics technologies, such as next-generation sequencing (NGS) provide the future opportunity to greatly expand the range of pathogens screened in donors, and to better monitor blood and transplant recipients for potential TTIs. A broader screening capability would enable blood banks to rapidly and effectively respond to new pandemic pathogens. However, the value of their future application for donor screening will require a much better understanding of the natural histories and potential disease associations of human virome components and other viruses incidentally detected on NGS screening. Furthermore, while genomic-based detection and ELISAs for pathogen-specific antibody can be readily applied for screening and excluding conventional pathogens, these are incapable of detecting and preventing transmission of proteinopathies, such as Creutzfeldt-Jakob disease (CJD) where the infectious agents possess no nucleic acid genome. The recent evidence for transmission of variant CJD in the UK through blood and plasma transfusion, and potential more extensive transfusion transmission of the amyloid disease, cerebral amyloid angiopathy, present potential existential threats to the ideal of complete blood safety if these findings are confirmed. A better understanding of the nature of “protein-only” transmissible agents in the aetiology of several forms of neurodegenerative disease is urgently required.