This review describes the recent developments in the applicability and clinical significance of epitope matching in kidney transplantation. As incremental human leukocyte antigen (HLA) mismatches are associated with increased risk of rejection and allograft loss, HLA-matching remains one of the standard immunological triage tests to determine transplant suitability. Advancements in tissue-typing techniques have led to innovative concepts of HLA-matching at the epitope level. Epitopes are configurations of polymorphic amino acid residues that are recognized by B cells, and antibodies reactive with these epitopes lead to rejection and/or premature allograft loss. Even though there is substantial advancement in the characterization and understanding of epitopes, evidence supporting the added clinical benefit of epitope matching over traditional antigen matching and the ability to identify clinically relevant immunogenic epitopes remains poorly defined. We present an overview of the evidence surrounding the immunogenicity of mismatched donor epitopes and the applicability of HLA epitope matching in kidney transplantation. A better understanding of the immunogenicity and structural characteristics of HLA epitopes will guide clinicians to integrate epitope matching as an important parameter for donor selection in kidney transplantation.