In this review, we discuss the current knowledge on the contribution of the NKG2D–NKG2DL signaling axis during intestinal inflammation, type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, where the role of NKG2D has been associated either by aberrant expression of the receptor and its ligands and/or by functional data in corresponding mouse models. Here, KLRK1 is linked to multiple sclerosis.