Monitoring and managing alloimmunization are among the primary functions of the clinical transfusion medicine laboratory. However, despite hundreds of different blood group antigens that vary from person to person, only a minority of transfusion recipients become alloimmunized. Currently, there are no tests that predict which patients will become alloimmunized. Moreover, there are no therapeutic interventions to prevent alloimmunization (outside of RhD immune globulin) besides phenotypic matching. Understanding the biologic factors that regulate alloimmunization may allow the generation of clinical tests with predictive capabilities and provide a rational basis for developing therapeutic interventions. This article summarizes recent advances in understanding alloimmunization, with a focus of identifying future directions in laboratory testing and management of transfusion. In addition to analyzing humoral alloimmunization, potential extensions of transfusion medicine to sequelae of cellular immunization are explored.