Extensive studies have been performed to clarify the processes during which mesenchymal stem cells (MSCs) differentiate into their lineage fates. In vitro differentiation of MSCs into distinct lineages have attracted the focus of a large number of clinical investigations. Although the gene expression profiling during differentiation of MSC toward bone, cartilage, and adipocytes is well established, the master regulators by which MSC fate can be controlled are not entirely determined. During differentiation of MSCs into a special cell fate, epigenetic mechanisms considered as the primary mediators that suppress the irrelevant genes and activate the genes required for a specific cell lineage. This review dedicated to addressing the changes of various epigenetic mechanisms, including DNA methylation, histone modifications, and micro-RNAs during chondrogenic and adipogenic differentiation of MSC.