We summarize recent findings linking inflammatory hypoxia to chromatin modifications, in particular to repressive histone signatures. We focus on the role of Hypoxia-Induced Factor-1 in promoting the activity of specific histone demethylases thus deeply modifying chromatin configuration. The consequences of these changes are depicted in terms of gene expression and cellular phenotypes. We finally integrate available data to introduce novel speculations on the relationship between inflammation, histones, and DNA function and integrity.