Major histocompatibility complex class I-specific inhibitory receptors on natural killer cells prevent the lysis of healthy autologous cells. The outcome of this negative signal is not anergy or apoptosis of natural killer cells but a transient abortion of activation signals. The natural killer inhibitory receptors fulfill this function by recruiting the tyrosine phosphatase SHP-1 through a cytoplasmic immunoreceptor tyrosine-based inhibition motif. This immunoreceptor tyrosine-based inhibition motif has become the hallmark of a growing family of receptors with inhibitory potential, which are expressed in various cell types such as monocytes, macrophages, dendritic cells, leukocytes, and mast cells. Most of the natural killer inhibitory receptors and two members of a monocyte inhibitory-receptor family bind major histocompatibility complex class I molecules. Ligands for many of the other receptors have yet to be identified. The inhibitory-receptor superfamily appears to regulate many types of immune responses by blocking cellular activation signals.