NKG2D is an important immunosurveillance receptor that triggers a unique signal transduction pathway resulting in a variety of functional outcomes. NKG2D couples to the non-ITAM-containing DAP10 and initiates at least two signaling branches that are both required for cytotoxicity. Transformed, infected, or healthy cells can express NKG2D ligands, and NKG2D⁺ lymphocytes can be unaffected, costimulated, or fully activated by the NKG2D-ligand interaction. The NKG2D-mediated response can be modulated by factors such as cytokine milieu and possibly the particular ligand expressed. Thus, this nontraditional NKG2D-DAP10 initiated signal pathway enables lymphocytes to differentially respond to ligands based on the cellular environment.