The spatial association between genomic DNA and histone proteins within chromatin plays a key role in the regulation of gene expression and is largely governed by post-translational modifications to histone proteins, particularly H3 and H4. These modifications include phosphorylation, acetylation, and mono-, di-, and tri-methylation, and while some are associated with transcriptional repression, acetylation of lysine residues within H3 generally correlates with transcriptional activation. Histone acetylation is regulated by the balance between the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). In skeletal muscle, the class II HDACs 4, 5, 7, and 9 play a key role in muscle development and adaptation and have been implicated in exercise adaptations. As just one example, exercise results in the nuclear export of HDACs 4 and 5, secondary to their phosphorylation by CaMKII and AMPK, two kinases that are activated during exercise in response to changes in sarcoplasmic Ca2+ levels and energy status, in association with increased GLUT4 expression in human skeletal muscle. Unraveling the complexities of the so-called “histone code” before and after exercise is likely to lead to a greater understanding of the regulation of exercise/activity-induced alterations in skeletal muscle gene expression and reinforce the importance of skeletal muscle plasticity in health and disease.