Signal regulatory proteins (SIRPs) constitute a family of transmembrane glycoproteins with extracellular Ig-like domains. Several SIRP family members have thus far been identified on myeloid and other cells in man, mouse, rat, and cattle. In the present study, we provide a description of the SIRP multigene family, including a number of previously undescribed SIRP genes, based on the complete genome sequences of various mammalian and bird species. We discuss this information in the context of the known immunological properties of the individual SIRP family members. Our analysis reveals SIRPs as a diverse multigene family of immune receptors, which includes inhibitory SIRPα, activating SIRPβ, nonsignaling SIRPγ, and soluble SIRPδ members. For each species, there appears to be a single inhibitory SIRPα member that, upon interaction with the “self” ligand CD47, controls “homeostatic” innate immune effector functions, such as host cell phagocytosis. The activating SIRPβ proteins show considerable variability in structure and number across species and do not bind CD47. Thus the SIRP family is a rapidly evolving gene family with important roles in immune regulation.