Allogeneic hematopoietic cell transplantation (HCT) is often the only curative treatment option for patients with malignant and non-malignant hematological diseases. There is striking evidence that immunological Graft-versus-Leukemia (GvL)-reactions efficiently eradicate malignant cells after transplant. After HLA-matched HCT both the beneficial GvL-effect and the detrimental Graft-versus-Host Disease (GvHD) are mediated by donor derived T-cells specific for minor histocompatibility antigens (mHag) that differ between patient and stem cell donor. In addition, tumor-specific antigens can also be targeted and contribute to GvL-reactivity. This review summarizes the state-of-the-art knowledge on mHag and presents the potential therapeutical options on example of the mHag HA-1. HA-1 is currently the best characterized mHag and particularly attractive for immunotherapy due to the restricted expression on hematopoietic cells and on some solid tumors but not on cells involved during GvHD. This would allow amplifying the endogenous GvL-effect and selectively targeting malignant HA-1-positive cells without causing GvHD. HA-1-specific immunotherapy in eligible patient and donor pairs may range from vaccination with the immunogenic HA-1 peptide to the infusion of HA-1-specific cytotoxic T-cells (adoptive immunotherapy).