Chronic graft loss due to antibody-mediated rejection (AMR) and the difficulty of re-transplanting highly sensitized patients are two of the major long-term challenges in pediatric renal transplantation. Treatments for AMR are often ineffective and desensitization protocols can be a high risk, making prevention a highly appealing strategy. Insights into the structural determinants of humoral alloantigenicity present an exciting opportunity to reassess our current paradigm of tissue matching and potentially preventing these complications. We review the theory behind human leukocyte antigen (HLA) B cell epitopes and the various systems that have been proposed to define them, including eplets. There is a growing body of clinical evidence suggesting that epitope-based tissue matching may be superior to traditional HLA antigen matching at predicting a range of clinical outcomes. However, additional studies are required to better understand the biological relevance of these systems of defining epitopes and their role in pediatric transplantation.