Recent studies have demonstrated that epigenetic mechanisms may play a pivotal role in the pathogenesis and development of Alzheimer''s disease (AD). Acetylation of histones and non-histone proteins pivotally modulate gene expression and signaling. Histone deacetylase inhibitors are recently suggested to act as neuroprotectors by enhancing synaptic plasticity and learning and memory of AD. HDAC2 is required for neurogenesis. HDAC2 is expressed in the hippocampus suggests a possible role in learning and memory, which negatively regulates learning and memory formation, as well as modulate synaptic plasticity and the number. HDAC2 associates with neurodegenerative impairment. The used HDACIs recently are wide-spectrum drugs, without specificity. Analysis of the HDAC2 unique effects are necessary for the rational design and testing of drug specificity in vivo.