From blood donor collection to transfusion of the recipient, there are several layers of protection of the blood supply. These measures combined with huge progresses over the three past decades in pathogen discovery and blood testing for specific pathogens (human immunodeficiency virus (HIV), hepatitis B (HBV) and C (HCV) viruses, Human T-cell leukemia virus (HTLV)), provide the greatest safety. With the implementation of serological and molecular testing, at least in high-income countries, transfusion-transmitted infections have become extremely rare. However, for pathogen agents, which are not tested and especially those which are responsible for emerging infectious disease, it became apparent that full control of infectious disease had not been achieved. In addition, the immune status of the recipient has also an impact in the outcome of infectious diseases transmitted by transfusion. Blood safety is based on several measures: education and deferral of donors with risk factors for transmissible disease, blood testing, pathogen reduction interventions, and patient blood management. This paper proposes a review of the residual risk of transmission of infectious diseases by transfusion and of the additional interventions able to further reduce it.