NK cells are primed to kill by several activating receptors. Killing of autologous cells is prevented as NK cells co-express inhibitory receptors for self-MHC class I molecules. Human NK cells discriminate between different allelic forms of MHC molecules via killer cell immunoglobulin-like receptors (KIRs), which are clonally distributed, and each cell in the repertoire bears at least one receptor that is specific for self-MHC class I molecules. Consequently, when faced with mismatched allogeneic targets, NK cells in the repertoire will sense the missing expression of self-MHC class I alleles and will mediate alloreactions. Recent studies in murine transplant models and data from mismatched haematopoietic transplant trials demonstrate MHC class I mismatches, which generate an alloreactive NK-cell response in the graft-versus-host direction, eradicate leukaemia, improve engraftment and protect against T-cell-mediated graft-versus-host disease.