Multichain immune recognition receptors (MIRRs) represent a family of surface receptors that is expressed on different cells and that transduces extracellular signals, leading to many biological responses. The most intriguing common structural feature of MIRR family members is that the extracellular recognition domains and the intracellular signaling domains are located on separate subunits. It is not clear how extracellular ligand binding triggers MIRRs and initiates intracellular signal-transduction processes. In this article, I suggest that the structural similarity of the MIRRs provides the basis for the similarity in the mechanisms of MIRR-mediated transmembrane signaling. This hypothesis assumes that the therapeutic strategies learned from a novel mechanistic model of MIRR-mediated signal transduction, the signaling chain homo-oligomerization model, are generalized for this entire family and have important implications for the treatment of many disorders that are mediated by immune cells, including HIV.