Natural killer group 2, member D (NKG2D) is an activating receptor present on the surface of natural killer (NK) cells, some NKT cells, CD8(+) cytotoxic T cells, gammadelta T cells, and under certain conditions CD4(+) T cells. Present in both humans and mice, this highly conserved receptor binds to a surprisingly diverse family of ligands that are distant relatives of major histocompatibility complex class I molecules. There is increasing evidence that ligand expression can result in both immune activation (tumor clearance, viral immunity, autoimmunity, and transplantation) and immune silencing (tumor evasion). In this review, we describe this family of NKG2D ligands and the various mechanisms that control their expression in stressed and normal cells. We also discuss the host response to both membrane-bound and secreted NKG2D ligands and summarize the models proposed to explain the consequences of this differential expression.