The mammalian α- and β-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 α-globin gene, including regions that flank and interrupt the coding sequence, and have compared this sequence with the sequences of the two mouse β-globin genes (Konkel, Tilghman and Leder, 1978; Konkel, Maizel and Leder, 1979). Like the two β genes, the α 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 α and β genes conserve considerable (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 diverged β genes and the long separate α 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.