Natural killer (NK) cells function through a diverse array of cell-surface natural killer receptors (NCRs). NCRs specific for classical and non-classical MHC class I proteins, expressed in complex patterns of inhibitory and activating isoforms on overlapping, but distinct, subsets of NK cells, play an important role in immunosurveillance against cells that have reduced MHC class I expression as a result of infection or transformation. Another NCR, NKG2D, is an activating NCR first identified on NK cells, but subsequently found on macrophages and a variety of T cell types. NKG2D ligands in rodents include the MHC class I-like proteins RAE-1 and H60 and, in humans, ULBPs and the cell stress-inducible proteins MICA and MICB. NKG2D-MIC and -RAE-1 recognition events have been implicated in anti-viral and -tumor immune responses. Crystallographic analyses of NKG2D-MICA and -RAE-1 complexes reveal an unusual mode of recognition that apparently tolerates a surprising degree of ligand plasticity while generating affinities that are among the strongest TCR- or NCR-ligand affinities, thus, far described.