The phylogeny of vertebrate alpha-fetoprotein (AFP) was surveyed in the phylum Chordata, including subphyla, agnatha, and Gnathostoma. A molecular taxonomic approach was undertaken based on biochemical, endocrinological, immunological, and physiological criteria previously documented for AFP. These published data were then discussed in light of their position and relationship in the albuminoid gene superfamily derived from GenBank. The phylogeny of the AFP molecule should prove useful for investigators seeking markers for animal models of human diseases, serological cross-reactivity between AFP molecular species, identification of larval or fetal protein homologs of AFP, and provide strategies for biochemical purification and physiological studies. The phylogeny of AFP in vertebrates was surveyed from the cyclostomata (lamphrey) to the mammals, including sharks, bony fishes, amphibians, reptiles, and birds. A trend was denoted, from lower to higher animal forms, in a size reduction and separation of AFP-like albumin molecular moieties from forms that resembled true albumin molecules. While the primitive lamphrey possesses a serum protein twice the size of mammalian albumin, the bony fishes, reptiles, and amphibians display two ALB-like molecules sharing amino acid sequence similarity to mammalian AFP. However, only one of the ALB-like molecules in the fish and amphibia is glycosylated. Although little has been published on reptilian AFP-like molecules, avian AFP has been investigated extensively following its detection and isolation for developmental studies involving immunology and neuroendocrinology. Finally, a plethora of knowledge exists in mammals following several decades of studies involving the isolation, purification, and characterization of AFP for use in physiological, immunological, and endocrinological research endeavors. In overview, a tendency or trend in down-sizing of an AFP-like albumin molecule and the separation of true albumin forms from a distinct fetal glycosylated form was observed. This seemed to occur in animal classes lacking a free-swimming larval form and possessing either highly differentiated extra-embryonic membranes or displaying a placenta intimately interfaced with the maternal tissues of the uterus.