Heterozygous loss-of-function mutations in KMT2D cause Kabuki syndrome, which is characterized by multiple malformations and intellectual disability. KMT2D (also known as MLL2) is a histone methyltransferase that targets lysine 4 of histone H3 (H3K4) to promote an open chromatin state. Mice with a heterozygous loss-of-function mutation in Kmt2d are known to have hippocampal memory defects. Now, Hans Bjornsson and colleagues characterize a new mouse model of Kmt2d haploinsufficiency and test the potential effectiveness of histone deacetylase inhibitor (HDACi) therapy (Sci. Transl. Med. 6, 256ra135, 2014). The authors show that Kmt2d+/βGeo mice have hippocampal memory defects and reduced neurogenesis, with loss of H3K4 trimethylation in the dentate gyrus granule cell layer of the hippocampus. They find that HDAC inhibitors, which promote an open chromatin state, increase H3K4 trimethylation in vitro in Kmt2d+/βGeo cells and that treatment of Kmt2d+/βGeo adult mice with the HDAC inhibitor AR-42 for 2 weeks corrects genome-wide H3K4 trimethylation in the granule cell layer to normal levels. Interestingly, AR-42 treatment improved measures of hippocampal memory in both Kmt2d+/+ and Kmt2d+/βGeo mice. This work suggests that some of the neurological deficits due to KMT2D haploinsufficiency may be treatable with postnatal HDAC inhibitor therapy.