Subtle alterations in synaptic function contribute to the pathophysiology associated with several neuropsychiatric diseases. Modifications in synaptic vesicle trafficking can cause frequency-dependent changes in neurotransmission, alter information coding in neural circuits, and affect long-term plasticity. Rett syndrome, a neurodevelopmental disorder that arises from mutations in the methyl-CpG-binding protein-2 (MeCP2) gene, is a salient example for such a disease state in which synaptic transmission-in particular, spontaneous neurotransmission and short-term synaptic plasticity, have been altered. MeCP2 is widely believed to be a transcriptional repressor that silences methylated genes. Recent studies have identified synaptic deficits associated with the loss of MeCP2 in several brain regions, including the hippocampus. These findings suggest a synaptic basis for neurological symptoms associated with Rett syndrome and suggest an important role for transcriptional repression in the regulation of neurotransmission. These studies also highlight the importance of histone deacetylation and DNA methylation, two key epigenetic mechanisms in controlling synaptic function. These mechanisms are essential for chromatin remodeling in neurons as well as for repression of gene activation by MeCP2 and related methyl-binding proteins. Future work focusing on the regulation of DNA methylation and histone deacetylation by synaptic activity and how these epigenetic alterations affect neurotransmission will be critical to elucidate the mechanisms underlying Rett syndrome. In addition, this work will also help delineate a key pathway that regulates properties of neurotransmission in the central nervous system that may underlie additional neuropsychiatric disorders.