Epigenetic regulation is crucial to all aspects of neurodevelopment and is therefore associated with neurological disorders. In particular, gene regulation by 5-hydroxymethylcytosine (5-hmC) is essential throughout neurodevelopment, spurning interest in identifying a role for 5-hmC in neurodevelopmental and neurodegenerative disorders, and mental illness. Differential global hydroxymethylation patterns are evident in epilepsy, whereas regional changes in 5-hmC patterns are associated with autism, including those within autism candidate genes and in pathways relevant to synapse development. In patients with bipolar disorder and schizophrenia, differential 5-hmC levels are seen in genes involved in neuronal maturation and functioning. Further, differential hydroxymethylation of genes involved in neuronal growth/maturation, neurogenesis, and synaptic processes is seen in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Together, these studies point to an important regulatory role for hydroxymethylation of genes involved in neuronal function and brain development, which contributes to the pathology of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.