Abstract The covalent modification of eukaryotic DNA by methylation of the 5′ carbon of cytosine residues is frequently associated with transcriptional silencing. In mammals, a potential mechanism for transducing DNA methylation patterns into altered transcription levels occurs via binding of methyl-CpG-binding domain (MBD) proteins. Mammalian MBD-containing proteins bind specifically to methylated DNA and recruit chromatin-modifying complexes containing histone deacetylase activities. Sequence similarity searches reveal the presence of multiple proteins in plants containing a putative MBD. Outside of the MBD itself, there is no sequence relationship between plant and mammalian MBD proteins. The plant MBD proteins can be divided into eight classes based on sequence similarity and phylogenetic analyses of sequences obtained from two complete genomes (rice [Oryza sativa] and Arabidopsis [Arabidopsis thaliana]) and from maize (Zea mays). Two classes of MBD proteins are only represented in dicot species. The striking divergence of plant and animal MBD-containing proteins is in stark contrast to the amino acid conservation of DNA methyltransferases across plants, animals, and fungi. This observation suggests the possibility that while plants and mammals have retained similar mechanisms for the establishment and maintenance of DNA methylation patterns, they may have evolved distinct mechanisms for the interpretation of these patterns.