ABSTRACT Ligand binding to the multichain immune recognition receptors (MIRRs) leads to receptor triggering and subsequent lymphocyte activation. MIRR signal transduction pathways have been extensively studied, but it is still not clear how binding of the ligand to the receptor is initially communicated across the plasma membrane to the cells interior. Models proposed for MIRR triggering can be grouped into three categories. Firstly, ligand binding invokes receptor clustering, resulting in the approximation of kinases to the MIRR and receptor phosphorylation. Secondly, ligand binding induces a conformational change of the receptor. Thirdly, upon ligand-binding, receptors and kinases are segregated from phosphatases, leading to a net phosphorylation of the receptor. In this review, we focus on the homodclustering induced by multivalent ligands, the heterodustering induced by simultaneous binding of the ligand to the MIRR and a coreceptor and the pseudodimer model.