Skeletogenesis occurs continuously during the lifespan of vertebrate organisms. In development, the skeleton is patterned and modeled until each bone achieves its optimal shape and full size. During adults, the skeleton is remodeled to maintain strength and release calcium. The bone-resorbing and bone-forming activities of osteoclasts and osteoblasts, respectively, are tightly coupled to maintain optimal skeletal health; however, during aging and disease, these cells can become uncoupled, adversely affecting skeletal health and strength. Histone deacetylases have emerged as important regulators of endochondral bone formation, osteoblast maturation and osteoclast survival. Histone deacetylases are inhibited by small molecules that are approved and/or in clinical trials as cancer therapeutic drugs or anti-epileptic agents. In this article, the roles of histone deacetylases and effects of histone deacetylase inhibitors on bone and cartilage cells are reviewed.