Blood transfusion is remarkably safe in high-income countries (HICs), where safeguards have long protected the blood supply against the major transfusion transmissible infections (TTIs). Globally, surprisingly few pathogens have been implicated in transfusion transmitted infection and most pathogens do not merit specific intervention. Nonetheless, pathogens are emerging much more frequently than is often appreciated, thus necessitating constant vigilance and individual assessment of transfusion-associated risk. Factors that inform the need for intervention include the ramifications (i.e., severity) of infection with a given pathogen, the likelihood of detection in the absence of a defined intervention, tolerance of standard processing and storage conditions (e.g., refrigeration), transfusion transmissibility and clinical penetrance (i.e., development of symptoms following transfusion transmission). Different approaches that have been used to protect the blood supply include donor selection and risk-based deferral, laboratory screening (i.e., using highly sensitive and specific serological and/or molecular assays), bacterial culture (platelets) and pathogen reduction (PR). Each approach has both strengths as well as limitations, whereby strategies are devised to meet national or regional risk, while balancing available resources. TTIs, as a direct reflection of blood transfusion safety, highlight a World divided. In HICs, hypervigilance is increasingly disproportionate to risk; this has contributed to policies and interventions that have been wasteful, incurring enormous cost at marginal-if any-clinical gain. By contrast, many of the routine measures regarded as effective in HICs are conspicuously deficient or even absent in lowand middle-income countries (LMICs) where blood transfusion thus remains a major mode of disease transmission.