Multi-chain immune recognition receptors (MIRRs) on T cells, B cells, mast cells and basophils function to transduce signals leading to a variety of biologic responses. These receptors are complexes formed by the association of immunoglobulin-like recognition subunits and signal-transducing subunits. How extracellular ligand binding initiates intracellular signal transduction processes is not clear, and little structural or biochemical information is available for the spatiotemporal organization of this key event in immune cell activation. Here, the current progress in studying this important aspect of cellular signaling is reviewed.