T and NK cell subsets play a crucial role in the immune surveillance designed to fend off dangerous pathogens while leaving endogenous cells untouched. However, occasionally T cells do initiate an attack against self and are therefore termed autoreactive. Moreover, both NK and T cells can be stimulated by danger signals released by cells under "stress", i.e. infection, ongoing necrotic cell death, etc. Consequently, the inappropriate triggering of danger signals, or a failure to switch these off once the immune response has been resolved, can have serious consequences for the host. Ligands for the activating receptor NKG2D (natural killer group 2 member D) are such key danger signals that are presented by "stressed" cells. In this review, we discuss the current knowledge on NKG2D and its ligands in the context of autoimmune diseases and immune-mediated diseases that inadvertently target endogenous cells and/or tissue.