Epigenetic mechanisms have rapidly and controversially emerged as silent modulators of host defenses that can lead to a more prominent immune response and shape the course of inflammation in the host. Thus, the epigenetics can both drive the production of specific inflammatory mediators and control the magnitude of the host response. The epigenetic actions that are predominantly shown to modulate the host defense against microbial pathogens are DNA methylation, histone modification and the activity of non-coding RNAs. There is also growing evidence that opportunistic chronic pathogens, such as Porphyromonas gingivalis, as a microbial host subversion strategy, can epigenetically interfere with the host DNA machinery for successful colonization. Similarly, the novel involvement of small molecule ‘danger signals’, which are released by stressed or infected cells, at the center of host–pathogen interplay and epigenetics is developing. In this review, we systematically examine the latest knowledge within the field of epigenetics in the context of host-derived danger molecule and purinergic signaling, with a particular focus on host microbial defenses and infection-driven chronic inflammation.