Short-term and longitudinal studies have shown that endurance exercise training extends life expectancy and reduces risk for many chronic disorders, including obesity, insulin resistance and type 2 diabetes (Hawley, 2004). Endurance exercise training orchestrates numerous morphological and metabolic adaptations in skeletal muscle, including mitochondrial biogenesis and an enhanced capacity to oxidize glucose and fats (Hawley, 2004). We have previously utilized global transcriptome expression technologies such as oligonucleotide arrays, targeted gene expression analysis, etc., to demonstrate that these changes are the culmination of transcriptional adaptations induced with individual acute bouts of endurance exercise (Mahoney et al. 2005). What has received less attention is how alterations in exercise-mediated DNA transcription are a function of post-translational modifications of histone proteins, which regulate transcriptional repression and/or initiation via chromatin remodelling. Acetylation of histone 3, one of the four types of histones important for genomic DNA packaging, at lysine residues 9, 14 and 36 (H3K9/14/36) is associated with transcription initiation and elongation. Histone acetylation is modulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, which in turn can be regulated by post-translational modifications such as phosphorylation, ubiquitination-mediated proteosomal degradation, sumolation, etc. Potthoff and colleagues (2007) have illustrated that over-expression of HDAC5 is negatively correlated with endurance training-mediated adaptations in mouse skeletal muscle. It remains unknown how histone acetylation and HDAC activity are modulated in response to an acute bout of exercise in humans. McGee et al. (2009), in a recent article in The Journal of Physiology, sought to address this issue by examining the effects of an acute bout of exercise on histone 3 modification, in conjunction with analysing the regulation of class IIa HDAC enzymes (McGee et al. 2009). McGee and colleagues subjected young men to an acute bout of cycling exercise (60 min at ∼75%) (McGee et al. 2009). Muscle biopsies were obtained from the vastus lateralis muscle before and immediately after the exercise bout. Western blot analysis was carried out on nuclear and whole muscle extracts to access the global histone 3 acetylation and class IIa HDACs (isoforms 4, 5, 7 and 9) protein content in response to an acute bout of exercise. Real-time PCR was used to measure the mRNA content of the HDAC isoforms immediately post-exercise. The authors also measured global HDAC activity and immunoprecipitated ubiquitinated HDACs as a marker of HDAC targeted for proteasomal degradation. Lastly, phosphorylation-mediated activation of class IIa HDAC kinases, AMPK, PKD and CaMKII, were measured in whole muscle extracts.