The activity of myocyte enhancer factor 2 (MEF2) transcription factors is a critical driver of the pathological cardiac hypertrophy and remodeling processes that culminate in heart failure, in both acquired and genetic forms of the disease. Extensive studies in recent years have revealed that class IIa histone deacetylase (HDAC) isoforms, such as HDAC4 and HDAC5, act as signal-responsive repressors of nuclear MEF2 activity in cardiac myocytes and that their spatial regulation provides a key mechanism for the neurohormonal control of such activity. The compelling scheme that has emerged is that HDAC4 and HDAC5 are direct substrates for serine/threonine protein kinases of the Ca2+/calmodulin-dependent kinase family, and that the phosphorylation of conserved residues that flank nuclear localization signal domains in HDAC4/5 leads to their exclusion from the nucleus and consequent de-repression of MEF2 activity. Recent studies suggest that protein kinase A (PKA) may also regulate MEF2 activity through HDAC-mediated mechanisms, but in an opposing manner, by promoting HDAC5 nuclear retention or HDAC4 proteolytic cleavage. Furthermore, there is emerging evidence that HDAC nuclear localization may be regulated additionally by a novel, phosphorylation-independent mechanism, through redox-dependent modification of reactive cysteine residues in HDAC4. Finally, HDAC5 may directly interact with HDAC2, a class I HDAC that has itself been causally implicated in cardiac hypertrophy and remodeling, and alter its function through deacetylation. How these different pathways are integrated in the neurohormonal regulation of HDAC localization and function in cardiac myocytes is unclear, with the picture further complicated by the existence of regulatory crosstalk between relevant kinase signaling pathways. This presentation will discuss emerging evidence on the mechanism(s) through which clinically significant neurohormonal stimuli may trigger post-translational regulation of HDAC isoforms, with particular focus on the role of kinases, phosphatases and oxidative signalling.