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A renaissance for human leukocyte antigen (HLA) testing emerged with the understanding that donor-specific HLA antibodies play a significant role in long-term allograft survival. This renewed focus on donor/recipient histocompatibility led to a recent quest to decipher antibody responses or, as introduced into the transplantation lexicon, ‘HLA-epitope matching’.Whether matching is at the antigen or the epitope level, in-depth understanding of how histo-incompatibility leads to activation of an immune response is required. HLA-DQ donor-specific antibody (DSA) has the highest association with poor graft survival. However, HLA-DQ antigens and antibodies are understudied and significant gaps still exist in understanding the function of HLA-DQ in immune activation. Much of our knowledge about HLA class-II molecules is derived from studies performed on HLA-DR, whether it is crystallography, antigen processing and presentation analysis, or activation of T-cell signal-transduction pathways. Indeed, HLA-DQ molecules are less amenable for laboratory testing, but the limited studies that were performed indicate that HLA-DQ might have, at least to some extent, a different role compared with HLA-DR.This review highlights qualities of HLA-DQ that may be associated with different pathways of activating an immune response. Understanding the consequences of such differences may lead to better appreciation and significance of HLA-DQ for matching purposes.