Histone acetyltransferases and deacetylases are two groups of enzymes whose opposing activities govern the dynamic levels of reversible acetylation on specific lysine residues of histones and many other proteins. Gastrointestinal (GI) carcinogenesis is a major cause of morbidity and mortality worldwide. In addition to genetic and environmental factors, the role of epigenetic abnormalities such as aberrant histone acetylation has been recognized to be pivotal in regulating benign tumorigenesis and eventual malignant transformation. Here we provide an overview of histone acetylation, list the major groups of histone acetyltransferases and deacetylases, and cover in relatively more details the recent studies that suggest the links of these enzymes to GI carcinogenesis. As potential novel therapeutics for GI and other cancers, histone deacetylase inhibitors are also discussed.