Abstract The functional contributions of the α and γ subunit domains of the high affinity receptor for IgE (Fcε-RI) were determined following chimeric receptor aggregation. Chimeric receptors of the extracellular (EC) and cytoplasmic tail (CT) domains of FcεRI and the IL-2R p55 subunit (I) were constructed and stably expressed in RBL-2H3 cells. Signaling (inositol phosphate production, tyrosine phosphorylation, Ca2+ mobilization, and secretion of histamine and arachidonic acid metabolites) via α/γ/γ or I/γ/γ was similar to the native rat receptor, and both were shown to associate with endogenous FcεRIβ and FcεRIγ subunits. Therefore, the contributions of the EC domains could not be evaluated. The chimeras α/I/γ and I/I/γ were found to be single polypeptide chains, as they did not associate with β and γ. Signaling via α/I/γ resulted in the appearance of biochemical events common to the native receptor. Cross-linking I/I/γ elicited histamine release, [14C]arachidonic acid metabolites, tyrosine phosphorylation, Ca2+ mobilization, and only inositol trisphosphate production, which were not of a similar magnitude to the native FcεRI. No biochemical events were elicited by cross-linking α/I/I or I/I/I. These results demonstrate that both the FcεRIα EC domain and the FcεRIγ CT domain are essential for the FcεRI signaling process, and that while FcεRIIγ CT plays a critical role in FεRI signaling, the EC domain of FcεRIα has a major contribution in signaling, as well as a role in modulating the magnitude of the biochemical events.