Receptors for the Fc region of immunoglobulin G (IgG) are a structurally diverse group of molecules. Within the three FcγR families (FcγRI, FcγRII and FcγRIII), the presence of distinct genes and alternative splicing variants leads to a variety of receptor isoforms that are most strikingly different in the transmembrane and intracellular regions. An obvious example of structural variation in the transmembrane and cytoplasmic domains is observed in the FcγRIII family. FcγRIIIB, which is nearly identical to FcγRIIIA in the extracellular domains, lacks both transmembrane and cytoplasmic protein domains and is anchored to the cell through a glycosyl phosphatidylinositol anchor. Analysis of FcγRIII function presents a considerable challenge in understanding the role of different FcγR receptors in polymorphonuclear neutrophil (PMN) function. While one hypothesis for the role of FcγRIII in serves as a binding molecule which focuses the IgG ligand for more efficient recognition and intracellular signaling by FcγRII, recent observations from a number of laboratories suggest that FcγRIII on PMN can transduce signals across the membrane independent of ligand-dependent engagement of FcγRII. We will review these data and present recent data which suggest that the role of FcγRIII extends beyond direct initiation of functions to a more complex role of synergistic receptor interactions. These findings will be reviewed in the context of the experimental approaches that thave been used to examine the roles of FcγRII and FcγRIII on PMN function. © 1992 Humana Press Inc.