Discovery of a large family of Fc receptor-like (FCRL) molecules, homologous to the well-known receptors for the Fc portion of immunoglobulin (FCR), has uncovered an impressive abundance of immunoglobulin superfamily (IgSF) genes in the human 1q21-23 chromosomal region and revealed significant diversity for these genes between humans and mice. The observation that FCRL representatives are members of an ancient multigene family that share a common ancestor with the classical FCR is underscored by their linked genomic locations, gene structure, shared extracellular domain composition, and utilization of common cytoplasmic tyrosine-based signaling elements. In contrast to the conventional FCR, however, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression. Most importantly, there is no strong evidence thus far to support a role for them as Ig-binding receptors. These characteristics, in addition to their identification in malignancies and autoimmune disorders, predict a fundamental role for these receptors as immunomodulatory agents in normal and subverted B lineage cells. Copyright © 2007 by Annual Reviews. All rights reserved.