Phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TYH) are mixed-function oxidases that share many characteristic biochemical and immunological properties. The recent cloning and sequencing of full-length cDNAs for both human PAH and rat TYH allow detailed comparison of their primary structures. There is a high degree of homology between PAH and TYH on nucleic acid and amino acid levels. The pattern of homology suggests that these molecules are comprised of a homologous core containing the determinants for enzymatic activity and a nonhomologous region that contributes to substrate specificity and regulation. The degree of homology also suggests that these two proteins evolved from a common ancestor.