Antibody-mediated rejection in solid organ transplantation is associated with significant organ dysfunction and allograft loss. Donor-specific antibodies against human leukocyte antigens (HLAs) have been a major focus for research, clinical testing, and therapies. Recently, non-HLA autoantibodies to various endothelial antigens including angiotensin II type 1 receptor, endothelin-1 type A receptor, Major Histocompatibility Complex Class 1-Related Chain A, perlecan, and collagen V are emerging as both potential mediators of allograft dysfunction and targets for intervention. Incorporation of non-HLA antibodies into clinical practice is currently not standardized due to a lack of consensus regarding the pathogenic effects on the allograft. Treatment strategies for non-HLA antibodies are evolving and remain an area that warrants further investigation.