Histone acetylation is a prominent epigenetic modification of the central nervous system that is unequivocally associated with an increase in the rate of gene transcription. Because gene transcription, in turn, plays an important role in long-lasting forms of memory, histone acetylation generally favors long-term memory, whereas histone deacetylation impinges on it. Histone acetylation is also amenable to pharmacological interventions-predominantly by the use of histone deacetylase (HDAC) inhibitors-and has therefore spurred considerable interest as a putative target of cognitive enhancement. Because of the ubiquitous presence of histone acetylation, HDAC inhibitors have great potential not only to treat cognitive impairment resulting from neurodevelopmental and neurodegenerative disorders but also to serve as cognitive enhancers for the cognitively healthy. In this review, we summarize the state of the art of HDAC inhibitors as cognitive treatments or cognitive enhancers; describe a new model of their mode of action, epigenetic priming; and caution against their unsupervised usage, despite their overall great promise.