Immunoreceptor tyrosine-based inhibition motifs (ITIMs) consist of a 6-amino acid stretch (ILV)xYxx(LV). ITIMs are expressed in the intracytoplasmic domain of transmembrane receptors, which extinguish cell activation induced by receptors bearing immunoreceptor tyrosine-based activation motifs. The recent identification of new members of the ITIM-bearing receptor family (such as the signal-regulatory proteins) extends the ITIM concept to the negative regulation of growth factor- and oncogene-induced activation in nonhemopoietic cells. In addition, it appears that a feature of the family of ITIM-bearing receptors is the existence of noninhibitory/activatory counterparts devoid of intracytoplasmic ITIMs and characterized by the presence of a charged amino acid residue in their transmembrane domain.