One of the best characterized NK cell receptors is NKG2D, a highly conserved C-type lectin-like membrane glycoprotein expressed on essentially all NK cells, as well as on gammadelta-TcR+ T cells and alphabeta-TcR+ CD8+ T cells, in humans and mice. Here we review recent studies implicating NKG2D in T cell and NK cell-mediated immunity to viruses and tumors, and its potential role in autoimmune diseases and allogeneic bone marrow transplantation.