Diabetes, obesity, and metabolic syndrome represent the current global epidemic. In spite of the continuous development of related pharmaceuticals, complications of these conditions lower the patient's life quality and cause a burden on the health economy. Histone deacetylase inhibitors are slowly emerging as a line of management for several medical conditions. Many studies have described their potential role in diabetes, in terms of enhancing insulin secretion and decreasing insulin resistance. In obesity, these agents showed a very interesting role in converting white fat cells to their brown counterpart, as well as shifting the metabolic pathways toward less adiposity. Although these effects are characterized at the cellular and preclinical levels, few clinical studies have been reported. This chapter includes an overview of the relation between histone deacetylation and the development of diabetes and obesity, as well as the possible future role of histone deacetylase inhibitors in the management of these conditions.