NKG2D (NK group 2, member D) is an activating natural killer (NK) receptor, which is expressed on NK and CD8+ T cells. On NK cells, NKG2D elicits cytotoxicity and release of cytokines. On CD8+ T cells, it functions as a co-stimulatory molecule. The receptor recognizes several ligands including the major histocompatibility complex (MHC) class I chain-related molecules A (MICA) and B (MICB) as well as the UL16-binding proteins (ULBP). The diversity of NKG2D ligands is further increased by a high degree of genetic variability of the ligands. Recently, an amino acid exchange from valine to methionine at position 129 in MICA has been found to be associated with the outcome of allogeneic hematopoietic stem cell transplantation (HSCT), and the functional consequences of this specific genetic variation have been elucidated. The clinical associations found after HSCT were explainable by the functional differences of the MICA-129 variants. Herein, we discuss how the genetic polymorphisms of NKG2D ligands and NKG2D itself interact and may affect the outcome of HSCT and the susceptibility to other diseases, which have been associated with polymorphisms in the NKG2D signaling pathway.