Antibody-mediated mechanisms have a major impact on allograft function and survival. During the last decade, improved immunohistochemical and serologic diagnostic procedures have been developed to monitor antibody responses against human leukocyte antigens (HLA). Acute and chronic allograft rejection can occur in HLA-identical sibling transplants implicating the importance of immune response against non-HLA targets. Non-HLA, complement and noncomplement-fixing antibodies may be responsible for a variety of allograft injuries, reflecting the complexity of their acute and chronic actions. Non-HLA antibodies may occur as alloantibodies or autoantibodies. Their antigenic targets described, thus, far include various minor histocompatibility antigens, vascular receptors, adhesion molecules, and intermediate filaments. An analysis of the subtle mechanistic differences in the individual antibody responses directed against non-HLA may help to identify patients at particular risk for irreversible acute or chronic allograft injuries and improve overall outcomes. This review summarizes the current state of research, development in diagnostic and therapeutic strategies, discusses some emerging problems, and provides perspectives in the area of humoral response against non-HLA in solid-organ transplantation.