Immunoglobulins (Ig), a critical component of the adaptive immune system, are present in all jawed vertebrates and through sophisticated diversification mechanisms are able to recognize antigens of almost infinite diversity. During mammalian evolution, IgG has emerged as the predominant Ig isotype that is elicited upon antigenic challenge, representing the most abundant isotype present in circulation. Along with the IgG molecule, a family of specialized receptors has evolved in mammalian species that specifically recognize the Fc domain of IgG. These receptors, termed Fcγ receptors (FcγRs), are expressed on the surface of effector leukocytes and upon crosslinking by the IgG Fc domain mediate diverse immunomodulatory processes with profound impact on several aspects of innate and adaptive immunity. FcγRs share a high degree of sequence homology among mammalian species and the ancestral locus, where the genes that encode for FcγRs are mapped, can be traced back early in mammalian evolution. FcγRs also share a number of common structural and functional properties among mammalian species and utilize highly conserved motifs for transducing signals upon engagement. Despite the high homology of FcγRs in diverse mammalian species, human FcγRs exhibit unique features relating to the gene organization, expression pattern in the various leukocyte populations, as well as affinity for human IgGs. Such inter-species differences in FcγRs biology between humans and other mammalian species represents a major limitation for the interpretation of in vivo studies on human IgG function using conventional animal models.