The immune system influences disease outcome in a variety of infectious and noninfectious complications of transfusion, including transfusion-transmitted viral infections, transfusion-associated acute lung injury (TRALI), and posttransfusion alloimmunization. By studying how the immune system is regulated, we can begin to understand how to better develop therapeutic interventions targeted to transfusion-associated adverse outcomes. Studies on the role of regulatory T cells in the control of viral infections such as those caused by the West Nile virus will be presented. In addition, the role of microRNAs in down-regulation of immune responses through their ability to influence signaling cascades will be reviewed. Finally, the clinical implications of transfusion-related immune modulation will be discussed.