Diverse cellular functions, including inflammatory gene expression, DNA repair, and cell proliferation, are regulated by histone acetylation. Transcriptional coactivators possess intrinsic histone acetyltransferase activity, and this activity drives inflammatory gene expression and the development of tolerance in macrophages. Eleven histone deacetylases (HDACs) act to regulate the expression of distinct subsets of inflammatory/immune genes. Other proteins, particularly transcription factors, are also acetylated and are targets for deacetylation by HDACs and sirtuins, a group of protein deacetylases. HDAC inhibitors can further enhance inflammatory gene expression. However, the acetylation/deacetylation status of nonhistone proteins can also affect the overall expression pattern of inflammatory genes. HDAC2 expression and activity is reduced in lung macrophages, biopsy specimens, and blood cells from patients with severe asthma and smoking-induced asthma, as well as in patients with chronic obstructive pulmonary disease, perhaps accounting for the enhanced inflammation and reduced steroid responsiveness seen in these patients. Targeting specific enzymes involved in this process might lead to new therapeutic agents, particularly in situations in which current anti-inflammatory therapies are suboptimal.