Stimulation of natural killer (NK) cells is regulated by a complex balance of inhibitory and stimulatory receptors expressed by NK cells. However, the interaction of stimulatory receptors and their ligands is poorly understood. One stimulatory receptor, NKG2D, is expressed by all NK cells, stimulated CD8+ T cells, gammadelta T cells and macrophages. Recently, progress has been made in defining cellular ligands for NKG2D. Four different families of ligands have been identified in mice and humans, all of which are distantly related to MHC class I molecules. Some of the ligands are upregulated in transformed and infected cells, provoking an attack by the innate and adaptive immune systems. It appears that these "induced-self" ligands recognized by the NKG2D receptor may be a precedent for a new strategy of target cell recognition by the immune system.