Therapeutic monoclonal antibodies (mAbs) exert their effects via binding to specific target molecules, which is expected to show rare off-target adverse reactions. However, nonclinical evaluation of mAbs is difficult because they often lack reactivity toward orthologous targets in animals. During the nonclinical evaluation of mAbs, not only the target molecules but fragment crystallizable (Fc) receptors, which regulate the immune effector functions and pharmacokinetic properties of mAbs, should be considered. In this review, factors for extrapolating nonclinical study results to clinical settings are discussed by focusing on Fc receptors. The human Fcγ receptor family consists of FcγRI, IIa, IIb, IIIa, and IIIb; Fcγ receptors in laboratory animals are structurally and functionally different from those in humans. In addition, interactions between human IgG-Fc, a component of therapeutic mAbs, and animal Fcγ receptors are still not fully understood. With regard to neonatal Fc receptor (FcRn), related molecules comprising the FcRn family are not known; however, critical amino acid residues involved in IgG binding are different between human and mouse. In case of next-generation mAbs with a novel structure or mode of action, knowledge from related drugs is limited. To ensure safety of next-generation mAbs, a thorough understanding of the differences in Fc receptors among species and the interactions between mAbs and Fc receptors is required, and the appropriateness of the nonclinical study design should be carefully examined prior to conducting clinical studies.