Sensitization by previous pregnancies or transplants is considered unavoidable, but it is transfusions given to these patients that leads most often to broad sensitization. Both leukocytes and red cells carry a significant HLA antigen load, and residual leukocytes and/or red cell HLA may explain why leukocyte-reduced units are unable to prevent sensitization to any significant degree. Prevention of sensitization will require a more active effort to avoid blood transfusions, whenever possible. When transfusions are required, there is evidence that the use of HLA-matched blood or immunosuppression in selected situations may reduce sensitization, even in patients previously exposed to alloantigens. These additional measures are not logistically straightforward or devoid of risks and need to be confirmed by rigorous studies. However, remaining as passive observers when patients become broadly sensitized should no longer be considered an acceptable alternative for potential transplant recipients.