The transferrin receptor family is represented by at least seven different homologous proteins in primates. Transferrin receptor (TfR1) is a type II membrane glycoprotein that, as a cell surface homodimer, binds iron-loaded transferrin as part of the process of iron transfer and uptake. Other family members include transferrin receptor 2 (TfR2), glutamate carboxypeptidase II (GCP2 or PSMA), N-acetylated alpha-linked acidic dipeptidase-like protein (NLDL), N-acetylated alpha-linked acidic dipeptidase 2 (NAALAD2), and prostate-specific membrane antigen-like protein (PMSAL/GCPIII). We compared 86 different sequences from 24 different species, from mammals to fungi. Through this comparison, we have identified several highly conserved residues specific to each family not previously associated with clinical mutations. The evolutionary history of the TfR/GCP2 family shows repeated episodes of duplications consistent with recent theories that nondispensable, slowly evolving genes are more likely to form multiple gene families.