The development and function of neurons require the regulated expression of large numbers of very specific gene sets. Epigenetic modifications of both DNA and histone proteins are now emerging as fundamental mechanisms by which neurons adapt their transcriptional response to developmental and environmental cues. In the nervous system, the mechanisms by which extracellular signals regulate the activity of chromatin-modifying enzymes have just begun to be characterized. In this Review, I discuss how extracellular cues, including synaptic activity and neurotrophic factors, influence epigenetic modifications and regulate the neuronal transcriptional response. I also summarize additional mechanisms that induce chromatin remodeling events by combinatorial assembly of multiprotein complexes on neuronal gene promoters.