The histone deacetylase (HDAC) family of transcriptional co-repressors have emerged as important regulators of colon cell maturation and transformation. Pharmacological inhibitors of class I and II HDAC activity (HDACi) are potent inducers of growth arrest, differentiation and apoptosis of colon cancer cells in vitro and in vivo, implicating a role for these HDACs in tumor promotion. Consistent with this role, expression of several HDACs are upregulated in colon tumors, while downregulation of specific HDACs inhibits growth of colon cancer cells in vitro and intestinal tumorigenesis in vivo. This review focuses on the function and transcriptional mechanisms by which class I and II HDACs regulate colon cell maturation and transformation, and on the mechanisms by which HDACi induce growth arrest, differentiation and apoptosis of colon cancer cells. The emerging role of the class III HDAC, Sirt1, in colon cancer progression is also discussed.