Gregory L. Verdine Department of Chemistry Harvard University Cambridge, Massachusetts 02138 DNA methylation has come of age. For more than 40 years, it has been known that eukaryotes tag their DNA by the covalent addition of a methyl group to cytosine residues; however, until very recently, the functional significance of this modification has remained on a precariously specula- tive footing. A series of discoveries over the last few years has thrust DNA methylation firmly into the mainstream of biology and medicine, thereby invigorating the field with afirmlyestablished sense of mission. Fragile X syndrome, the leading cause of inherited mental retardation, has been traced to expansion and abnormal methylation of a triplet repeat, through which transcription of the FMR-7 gene becomes silenced (Trottier et al., 1993). Aberrant promoter methylation of tumor suppressor genes has now emerged as an epigenetic inactivation pathway contribut- ing to tumorigenesis; evidence increasingly supports the notion that ectopic methylation may play a broad role in gene inactivation and mutation in mammals (reviewed by Bestor and Coxon, 1993). Much excitement has revolved around the roleof DNA methylation in genomic imprinting, a phenomenon in which parental alleles of the same gene are expressed at unequal dosages (Barlow, 1993). Abnor- rnal expression of imprinted loci is now implicated in sev- eral human disorders (Ogawa et al., 1993; Rainier et al., 1993; Davies, 1992), and more instances seem likely to be discovered. The entire field of DNA methylation, with its foundations resting largelyon the strength of correlative clata, took both a collective breath of relief and a bold step forward with the direct demonstration of Li et al. (1992) that the DNA MTase gene is essential for development in mice. A molecular mechanism for spatiotemporal coupling of DNA replication and methylation has been suggested by the finding that DNA MTase interacts directly with the replication apparatus (Leonhardt et al., 1992). Just as these advances represent the dawning of a new era in the biology of DNA methylation, so does remarkable progress in the alter ego of this scientific problem-its chemistry-also foretell a bright future. A turning point in the chemistry of DNA methylation is ushered in by the cocrystal structure of a DNA methyltransferase bound co- valently to DNA, which is reported by Klimasauskas et al. (1994 [this issue of CeIj). More generally speaking, this