The methylation of vertebrate DNA at the 5-position of approximately 3-10% of its cytosine residues occurs in a sequence-specific and tissue-specific manner and has been implicated in the control of transcription. How these differences are established and how they mediate the initiation or maintenance of transcription are unknown. DNA methylation might also have other roles, such as modulating DNA replication, transposition, DNA repair or chromosome configuration. These other roles suggested for DNA methylation would be consistent with the finding that tissue-specific differences in methylation of certain gene regions, highly repeated satellite DNA sequences and whole genomes often do not correlate with transcriptional activity. For DNA methylation to modulate the expression, maintenance or duplication of chromosomes, there should be effector macromolecules, presumably proteins, which specifically recognize 5-methylcytosine (m5C) residues in DNA. We describe here the first identification of a mammalian protein that binds preferentially to m5C-rich DNA sequences.