Cognitive development is determined by both genetics and environment. One point of convergence of these two influences is the neural activity-dependent regulation of programs of gene expression that specify neuronal fate and function. Human genetic studies have linked several transcriptional regulators to neurodevelopmental disorders including mental retardation and autism spectrum disorders. Recent reports on two such factors, CREB-binding protein and methyl-CpG-binding protein 2, have begun to reveal how epigenetics and neuronal activity act to modulate the program of gene expression required for synaptic development and function.