Understanding the effect of DNA methylation requires an appreciation of the determinants responsible for gene expression. To this end, we and others have demonstrated the exquisite silencing properties of methylation-dependent repressors that belong to the methyl-CpG binding domain (MBD) protein family. It is crucial, to establish a direct connection between the remodelling events observed with the fragile X mental retardation gene 1 (FMR1) promoter if we are to understand the mechanism of control. In this paper contrasting but not mutually exclusive models are discussed, which conceptually and experimentally reflects an appreciation of the surrounding chromatin environment. Examining general transcription systems controlled by DNA methylation, proteins that recognize the methyl-CpG moiety and the enzyme that maintains methylation, a unified model of FMR1 gene silencing are discussed. (C) 2002 Elsevier Science (USA). All rights reserved.