Allergic transfusion reactions (ATRs) are a common complication of blood transfusions. Advances in transfusion medicine have significantly decreased the incidence of ATRs; however, ATRs continue to be burdensome for patients and problematic for providers who regularly order packed red blood cells and platelet transfusions. To further decrease the frequency of ATRs, routine premedication with diphenhydramine is common practice and is part of "transfusion culture" in a majority of institutions. In this article, we review the history, practice, and literature of transfusion premedication, specifically antihistamines given the adverse-effect profile. We discuss the rationale and original academic studies, which have supported the use of premedication for transfusions for decades. However, despite the common use of premedication to prevent ATRs, recent literature has not conclusively validated its use. In addition, the existing premedication that is routinely prescribed often causes a number of adverse effects. These findings have motivated the Moores Cancer Center (University of California, San Diego) to change its current transfusion premedication practices, particularly with regard to ATRs and first-generation antihistamines. We outline the preliminary development of an evidence-based and patient-specific approach to transfusion premedication, including the challenges and steps taken to revise inpatient premedication protocols. We plan to expand this protocol to the outpatient setting at a later date. Future efforts require a prospective validation of our presented transfusion premedication guidelines.