Technical advances combined with the deciphering of the human genome have facilitated the identification of the molecular nature of human minor histocompatibility (H) antigens. To date, it is believed that minor H antigens result from just any polymorphic protein, regardless of their functional properties. A closer look at the first series of autosomally encoded human minor H proteins reveals a striking functional relationship. Here, we propose that T cells generated after HLA-identical stem cell transplantation (SCT) for malignancies are likely to be directed towards peptides derived from minor H proteins involved in tumourigenesis. This novel insight has important consequences in the search for, and the use of, minor H antigens as immunotherapeutics in stem-cell-based immunotherapy of haematological malignancies and solid tumours.