Regulation of cellular responses by inhibitory receptors is crucial for proper function of the immune system. The prototype inhibitory immune receptors are major histocompatibility complex (MHC) class I binding killer-Ig like receptors (KIRs) present on effector cells such as natural killer (NK) cells and effector T cells. However, the recent identification of non-MHC class I ligands for inhibitory immune receptors, such as KLRG1, KLRB1 and LAIR-1, indicates that also MHC class I-independent inhibitory immune receptors play crucial roles in inducing peripheral tolerance. The presence of these receptors on many other immune cell types besides effector cells suggests that tight regulation of cell activation is necessary in all facets of the immune response in both normal and diseased tissue. Here, we review novel insights and implications of non-MHC class I ligand binding to inhibitory immune receptors. We give an overview of the known ligand-receptor pairs by grouping the ligands according to their properties and discuss implications of these interactions for the maintenance of immune balance and for the defense against tumors and pathogens.