Post-translational modifications (PTMs) are important for cellular functions. The regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is one of important PTMs for epigenetic control, protein activity and protein stability. The regulation of acetylation of the N-terminal histone tails of core histone affects gene expression. Two class I HDAC genes and two class II HDAC genes have been identified in the Magnaporthe oryzae genome. Treatment with Rpd3/Hda1 family (classical) HDAC inhibitor inhibited the appressorium differentiation of M. oryzae. Treatment with trichostatin A, a classical HDAC inhibitor, also decreased pathogenesis. Furthermore, analyses of HDAC mutants indicated that MoHda1 and MoHos2 were required for vegetative growth and conidiation, and MoHos2 was required for appressorium formation. Disruption MoRPD3 was unsuccessful, as in the case with Aspergillus nidulans RpdA. These data indicated that HDACs have important roles in the asexual differentiation of M. oryzae.