Replication-independent histone variants play an essential role in postmitotic neurons. Here, we review how the subtle sequence differences of histone variants compared to their canonical counterparts underly neuronal function. We focus on variants H3.3, H2A.Z, H2A.X, macroH2A, and H2BE; all of which contain divergent sequences that coordinate a diverse set of outcomes. In particular, we highlight their role in neuronal development, plasticity, and memory, with an emphasis on how single amino acid changes can mediate these complex functions. Lastly, we comment on an emerging field of study evaluating the link between histone variants and neurological disorders. Future studies of histone variants will be important to furthering our understanding of neuronal function.