The receptor for IgE (FceRI), a member of the multisubunit immune recognition receptor (MIRR) family, initiates signal transduction after these cell surface receptors are aggregated by an external antigen. A variety of experimental results provides strong evidence that this transmembrane signaling involves the association of aggregated IgE FceRI with specialized domains of the plasma membrane. Components of these membrane domains include lipids and lipid-anchored proteins that are characterized by their resistance to solubilization by non-ionic detergents and their co-redistribution with aggregated FceRI on cells. Our data from RBL-2H3 mast cells indicate that these interactions mediate tyrosine phosphorylation of aggregated IgE-FceRI by supplying a locally high concentration of the fatty acylated Lyn kinase, and possibly by excluding phosphatases. This model for signal initiation emphasizes membrane structure and selective protein-lipid interactions to facilitate functional coupling between proteins. The challenge remains to elucidate the molecular mechanisms for formation of membrane domains in cells such that functional receptor activation can be reconstituted from purified components.