The development of surgical techniques and the use of immunosuppressive agents can increase the lifespan of the graft in organ transplants. Nonetheless, donor specific and non-specific antibodies produced prior to transplantation cause both acute and chronic rejection and, consequently, graft damage. Non-HLA antibodies have started to attract attention as a result of the observation of rejections in patients whose cross match test results were negative and didn't have antibodies produced against donor specific and HLA panel. It has been determined that non-HLA antibodies cause both acute and chronic rejections, and may have different effects on the organ they target. These antibodies were first identified in 1995. Vascular receptors, adhesion molecules and intermediate filaments are among the targets of non-HLA antibodies. Many studies are available in literature investigating angiotensin type 1 receptor (AT1R), endothelin type A receptor (ETAR), collagen-V (Kol-V), K-alpha 1 tubulin (KA1T), perlecan (LG3) C-terminal fragment, associated with MHC class I polypeptide A and B. In addition, more non-HLA antibody targets can be identified and organ transplantation and graft survival studies can be developed. In this review, antigenic targets, treatment strategies and detection methods of non-HLA antibodies will be discussed.