Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2, serves as a histone methyltransferase toward histone H3K27 trimethylation and also recruits DNA methyltransferases to regulate gene expression and chromatin structure. Accumulating evidence indicates the critical roles of EZH2 in stem cell maintenance and cell fate decision in differentiation into specific cell lineages. In this article, we review the updated progress in the field and the potential application of EZH2 in regenerative medicine including nervous system, muscle, pancreas, and dental pulp regeneration.