Histone deacetylases (HDACs), which regulate transcription, seem to modulate cocaine reward behaviours, but the underlying mechanisms are unclear. A new study shows that in rodent striatal neurons, cocaine and cyclic AMP signalling, which is upregulated by cocaine, induce HDAC5 nuclear translocation. Such translocation is dependent on transient dephosphorylation of Ser279 in the HDAC5 nuclear localization signal. Mice overexpressing Ser279-non-phosphorylatable HDAC5 in the nucleus accumbens show impaired development of cocaine-induced reward behaviour in a cocaine-conditioned place preference assay. Thus, HDAC5 activity seems to limit the rewarding effects of cocaine, possibly via transcriptional effects.