Tau protein is one of the major microtubule-associated proteins of the vertebrate nervous system. Some kinds of isoforms, for example, six isoforms in humans, are generated from a single gene by alternative mRNA splicing. The expression of tau protein is widely believed to be developmentally and pathologically regulated. We examined developmental changes in tau protein from humans, rats, mice, and guinea pigs to determine the universal function of each isoform. Tau isoforms, composed of variants in the amino terminal and carboxyl terminal regions, gradually shifted through development in protein. The developmental changes in the carboxyl terminal region were found to be conserved in all species in which three-repeat tau isoforms were dominant in the fetus or neonate, while four-repeat tau isoforms were dominant in adult brain. On the other hand, the changes in the amino terminal region were not identical in these species. These observations were confirmed using isoform-specific antibodies which could discriminate the numbers of amino-terminus insertions and carboxy-terminus repeat insertions. Developmental regulation of 3- and 4-repeat tau isoforms may contribute to axonal development and neural plasticity.