NKG2D is a member of the NKG2 family of C-type lectin-like surface receptors. It is a homodimeric activating receptor expressed on natural killer (NK) cells, gamma/delta T-cells and CD8+ alpha/beta T-cells. NKG2D can mediate NK activation and cytotoxicity. NKG2D interacts with the stress-induced class I like molecules MICA, MICB and ULBPs expressed on target cells. Interaction of NKG2D and NKG2D ligands leads to NK cell activation (Cosman et al. 2001, Steinle et al. 2001, Long. 2002). In mice there are two alternatively spliced isoforms of NKG2D, designated NKG2D-S and NKG2D-L. DAP12 interacts with NKG2D-S, but not NKG2D-L, whereas the DAP10 adapter associates with both NKG2D-S and NKG2D-L (Gilfillan et al. 2002, Diefenbach et al. 2002). Humans only express an NKG2D-L isoform and exclusively associate with DAP10, and not DAP12 A Structural basis for the association of DAP12 with mouse, but not human, NKG2D (Rosen et al. 2004).