Minor histocompatibility antigens have to be considered as key molecules in the stem cell-based immunotherapy of malignancies. Allogeneic stem cell transplantation (SCT) is a well-established and effective therapy for advanced hematologic malignancies. The apparent powerful graft-versus-leukemia effect of SCT led clinicians to apply SCT for the treatment of metastatic solid tumors. The SCT-based graft-versus-tumor reaction in the allogeneic human leukocyte antigen-matched SCT setting is mediated by allo-immune effector cells directed against tumor-related target antigens. The target molecules involved in the allo-immune graft-versus-tumor reaction are tumor-specific antigens, tumor-associated antigens, and tissue-and cell-specific minor histocompatibility antigens. The power of the minor histocompatibility antigens in the human leukocyte antigen-identical, stem cell-based immunotherapy for malignancies is their “allo-ness.” As opposed to tumor-associated self antigens, the complexes of MHC and allo-target peptide are likely to be more immunogeneic than the major histocompatibility complex and self-target peptide complexes. Moreover, minor histocompatibility allo-antigens are not subject to self to lerance. Earlier minor histocompatibility antigens were seen as alien entities, disturbing the success of the so ideally matched organ and SCT donor-recipient combinations. To date, minor histocompatibility antigens can be set in the favorable light of useful tools for immunotherapy for cancer. The first clinical application of the hematopoietic minor histocompatibility antigens HA-1 and HA-2 is currently being explored in a stem cell-based setting for hematologic malignancies. Because HA-1 is also expressed on carcinoma cells, a stem cell-based vaccination trial for patients with metastatic breast or renal cancer is about to start as well. The immunotherapeutic potential of minor histocompatibility antigens demands serious searches for new minor histocompatibility antigens and analyses of their phenotype frequency, tissue distribution, and functional membrane expression. The minor histocompatibility antigens meeting the prerequisites for specific immunotherapy for malignancies, such as membrane expression and tissue and/or cell specificity, may offer the curative tools for stem cell-based immunotherapy for various hematologic and nonhematologic malignancies.