NKG2D is a type II transmembrane-anchored glycoprotein expressed as a disulfide-linked homodimer on the surface of all mouse and human natural killer cells (NK cells). Stimulation of NK cells through NKG2D triggers cell-mediated cytotoxicity and in some cases induces the production of cytokines. NKG2D binds to family of ligands with structural homology to MHC class I, however, unlike conventional MHC class I molecules, NKG2D ligands often display up-regulated surface expression on stressed cells and are frequently over expressed by tumors. Recent evidence clearly implicates that NKG2D recognition plays an important role in tumor immune surveillance and that NKG2D primarily acts to trigger perforin-mediated apoptosis. The data begin to place the NKG2D pathway into the context of other recognition-effector systems used by NK cells.