The mammalian alpha- and beta--globin genes are thought to have evolved from a common ancestral sequence by a duplication event that occurred over 500 million years ago. We have now determined the entire nucleotide sequence of a cloned mouse alpha--globin gene, including regions that flank and interrupt the coding sequence, and have compared this sequence with the sequences of the two mouse beta--globin genes (Konkel, Tilghman and Leder, 1978; Konkel, Maizel and Leder, 1979). Like the two beta genes, the alpha gene is interrupted by two intervening sequences at precisely homologous positions, suggesting that these interruptions were present and have been preserved throughout vertebrate evolution. While the alpha and beta genes conserve considerable (approximately 55%) sequence homology in their coding regions, this homology--with certain interesting exceptions--is lost in the highly divergent flanking and intervening sequences. These exceptions are short preserved sequences positioned in such a way that they might encode signals for transcriptional initiation, poly(A) addition and RNA splicing. Furthermore, a comparison of the recently divererged beta genes and the long separate alpha gene allows us to distinguish two clearly different modes of nucleotide sequence change in evolution: a fast mode which is characterized by drastic sequence alterations involving deletions and insertions, and a slow mode which preserves sequence homology to a large extent and involves mainly point mutations.