Macrophages are important player in defense against invading pathogens and their dysfunction is linked to most of inflammatory and autoimmune diseases. Inflammation is a normal and physiological response of the immune system against harmful stimuli such as infection and injury. However, when allowed to continue unchecked, under certain conditions it turns into autoimmune or inflammatory diseases, neurodegeneration, and carcinogenesis. Currently, several safe and effective anti-inflammatory drugs are available with many more drugs in the development pipeline, among which are histone deacetylase inhibitors. In this review we discuss how post-translational modifications of histones influence the innate and adaptive immunity through macrophage survival, proliferation, polarization and functional responses. We also discuss how emerging classes of pharmacological agents which developed for use as anti-cancer agents, have been applied as anti-inflammatory drugs to treat macrophage-mediated inflammatory and autoimmune diseases.