AbstractThe “chromogenome” is defined as the structural and functional status of the genome at any given moment within a eukaryotic cell. This article focuses on recently uncovered relationships between histone chaperones, post‐translational acetylation of histones, and modulation of the chromogenome. We emphasize those chaperones that function in a replication‐independent manner, and for which three‐dimensional structural information has been obtained. The emerging links between histone acetylation and chaperone function in both yeast and higher metazoans are discussed, including the importance of nucleosome‐free regions. We close by posing many questions pertaining to how the coupled action of histone chaperones and acetylation influences chromogenome structure and function. J. Cell. Physiol. 224: 289–299, 2010. © 2010 Wiley‐Liss, Inc.