Innate immune cells have complex signalling pathways for sensing pathogens and initiating innate immune responses against infection. These pathways are tightly regulated at different levels, including by epigenetic regulators. In this Review, we discuss studies revealing the epigenetic mechanisms, as well as the post-transcriptional and post-translational modifications by chromatin modifiers, that underlie the establishment of these signalling networks and the rapid induction of innate immune molecules during infection. We also discuss how pathogens use their own products, as well as host components, to target host epigenomes for immune evasion and survival. We describe the crosstalk between epigenetic regulators and new modulators, such as inflammation-specific metabolites, and how we might deconstruct dynamic chromatin patterns and identify critical chromatin modifiers of host-pathogen interactions.