Many advances in safety of blood transfusion relate to prevention of transfusion-transmitted infections (TTI). The development, standardization and implementation of an expanding array of immunoassays employed worldwide in routine screening of blood donated by voluntary blood donors, with exclusion of infected blood and their donors continue to reduce the risk of transmitting HBV, HCV, HIV-1/2, HTLV-I/II and Treponema pallidum infections. Nucleic acid tests (NAT) using enzymatic amplification of viral gene sequences have augmented the risk reduction in ‘‘window period’’ infections that are undetectable by the serological tests. The continuing risk of bacterial contamination, especially in platelet concentrates optimally stored at room temperature, has led to methods such as bacterial screening of platelets or pathogen reduction technologies to be adopted by some blood organizations. Besides the current effort devoted to microbial risk reduction, pathogen reduction technologies promise the theoretical reduction of the residual risk of known and emerging infectious agents. The effectiveness of the foregoing measures, international harmonization of practices and procedures, and continued hemovigilance portend best practice in transfusion medicine.