Many antigen receptors of the immune system belong to the family of multichain immune recognition receptors (MIRRs). Binding of ligand (antigen) to MIRR results in receptor phosphorylation, triggering downstream signaling pathways and cellular activation. How ligand binding induces this phosphorylation is not yet understood. In this Chapter, we discuss two models exploring the possibihty that kinases and phosphatases are intermingled on the cell surface. Thus, in resting state, MIRR phosphorylation is counteracted by dephosphorylation. Upon ligand binding, phosphatases are removed from the vicinity of the MIRR and kinases, such that phosphorylated MIRRs can accumulate (segregation models). In the first model, clustering of MIRRs by multivalent hgand leads to their concentration in lipid rafts where kinases, but not phosphatases, are localized. The second model takes into account that the MIRR-ligand pair needs close apposition of the two cell membranes, in cases where ligand is presented by an antigen-presenting cell. The intermembrane distance is too small to accommodate transmembrane phosphatases, which possess large ectodomains. Thus, phosphatases become spatially separated from the MIRRs and kinases (kinetic-segregation model).