Donor selection based on blood group phenotypes, and blood processing such as leukocyte-depletion, gamma-irradiation or washing to remove plasma, are approaches for therapeutic or preventive use to manage the immunological complications of transfusion. Indications for specific components are prescribed in guidelines provided by (inter)national Transfusion Societies. Although the use of guidelines and protocols is in line with modern medicine, these can create a state of tension with the political sense of values to improve the viral safety of blood products and with the commercial exploitation of pooled plasma-products.A century of blood transfusion therapy has facilitated cancer treatment and advanced surgical interventions. The transfusion product has improved progressively, although mostly in response to disasters such as wars and AIDS. Every blood transfusion interacts with the immune system of the recipient. There are, however, very few quantitative figures to estimate the consequences. This review is based on the available literature on the clinical consequences of transfusion induced immunization and modulation. To a large degree the clinical consequences of transfusion induced immune effects are still a mystery.A blood transfusion is a medical intervention, which in many cases remains experimental with respect to the benefit/risk ratio. Ideally, this uncertainty should be communicated to patients and every transfusion included in a study. Such studies preferentially should be randomized because the perceived need for transfusion is associated with clinical conditions with a worse prognosis than those that do not receive transfusion. This difference may mask the interpretation of the transfusion effect. Since the blood supply services in almost all Western countries have been reorganized and nationalized, or at least operate to national quality standards, the measurement of risk: benefit of transfusion, whether political or evidence-based, needs to be reconsidered. Differences in emphasis and responsibilities between transfusion providers and transfusion prescribers will drive the providers to political and liability criteria - ever safer products - that will increase hospital costs with undetermined clinical benefits.