The immunoreceptor tyrosine-based activation motif (ITAM) is the primary signaling domain used by classical immunoreceptors, such as the antigen receptors on B and T lymphocytes and the Fc receptors (FcRs) on myeloid cells. The ITAM is contained in the intracellular region of subunits associated with these receptors, often in pairs, or is part of the cytoplasmic domain of the receptors themselves. Data from many investigators have demonstrated that ITAMs are both necessary and sufficient for initiation of signaling downstream of all immunoreceptors. More recent reports indicate that ITAM signaling is used by additional receptors beyond the classical immunoreceptors: Cell adhesion molecules (integrins and PSGL-1), chemokine receptors (CXCR4), plexins, and lectin receptors all mediate immune cell function through ITAM-like signaling pathways. This convergence of intracellular signaling pathways in leukocytes illuminates the importance of tyrosine-based activation motifs in the immune system and suggests that inhibitors of ITAM signaling may have broader effects than originally envisioned.