AbstractMinor histocompatibility (H) antigens are key molecules driving allo‐immune responses in both graft‐versus‐host‐disease (GvHD) and in graft‐versus‐leukemia (GvL) reactivity in human leukocyte antigen (HLA)‐matched hematopoietic stem‐cell transplantation (HSCT). Dissection of the dual function of minor H antigens became evident through their different modes of tissue and cell expression, i.e. hematopoietic system‐restricted or broad. Broadly expressed minor H antigens can cause both GvHD and GvL effects, while hematopoietic system‐restricted minor H antigens are more prone to induce GvL responses. This phenomenon renders the latter group of minor H antigens as curative tools for HSCT‐based immunotherapy of hematological malignancies and disorders, in which minor H antigen‐specific responses are enhanced in order to eradicate the malignant cells. This article describes the immunogenetics of minor H antigens and methods that have been developed to identify them. Moreover, it summarizes the clinical relevance of minor H antigens in transplantation, with special regards to allogeneic HSCT and solid‐organ transplantation.