This review was derived from a presentation made on September 2, 2016, for the first Academy Day presented by the Working Party on Immunohematology at the International Society of Blood Transfusion (ISBT) Congress in Dubai. The focus of this review is on the clinical significance of alloimmunization in transfusion-specifically, the parameters that contribute to a clinically significant alloantibody. The areas of focus were as follows: Introduction, Technical Aspects, and Indications and Limitations. Each section contains a brief review of selected literature and experiential knowledge. Case reports are needed to collect data on current outcomes of incompatible transfusion. The ISBT Working Party on Rare Donors has developed a form to capture case-specific information.