In excitable tissues, the activity of plasmalemmal ion transporters is vital for the maintenance of normal electrical activity and ion gradients. In cardiac muscle, the transarcolemmal Na gradient established by the ubiquitous Na/K ATPase (Na pump) is essential not only for generating the rapid upstroke of the action potential but also for driving a number of ion exchange and transport processes critical for normal cellular function, ion homeostasis and the control of cell volume (1). The cardiac sodium calcium exchanger (NCX1), which is functionally coupled to the Na pump, similarly plays a vital role in the regulation of trans-sarcolemmal Ca fluxes in cardiac muscle, because it is the principal route by which Ca leaves the cell during diastole (2). Inappropriate NCX1 function contributes to cardiac contraction abnormalities and heart failure: reduced NCX1 activity reduces Ca removal and impairs relaxation, whereas overactive NCX1 unloads the intracellular Ca stores and impairs systolic function. Curiously, a common feature of regulation of both the Na pump and NCX1 is controversy regarding the roles and targets of protein kinases in their regulation. Phosphoregulation of NCX1 is an unresolved controversy. In the heart, phosphoregulation of the Na pump is now established to be through phosphorylation of the accessory protein phospholemman (PLM). Unphosphorylated PLM inhibits the Na pump, and phosphorylation by PKA (at S68) or PKC (at S63, S68 and T69) activates the pump (1). As well as being phosphorylated, PLM is palmitoylated at two cysteines, C40 and C42 in an intracellular α-helix adjacent to its transmembrane domain. Palmitoylation of PLM inhibits the Na pump, but intriguingly palmitoylation of PLM is promoted by its phosphorylation at S68 by PKA (3). Hence one post-translational modification of PLM that activates the Na pump promotes a second, which inhibits it. Although the DHHC-PAT(s) that palmitoylate PLM (or any pump subunits – see below) are yet to be identified, another important regulator of the palmitoylation status of PLM is the redox state of the cell. Cellular glutathione status is linked to PLM palmitoylation state by the anti-oxidant protein peroxiredoxin 6, which depalmitoylates PLM in a glutathione dependent manner. In addition, mitochondrial redox stress leads to a reduction in PLM palmitoylation, with a concomitant increase in its glutathionylation at C42. The presence of PLM (or other members of the FXYD gene family to which it belongs, which are also palmitoylated) in the Na pump enzyme complex therefore provides a means to link pump activity to cellular redox / metabolic state, through a balance between its phosphorylation, palmitoylation, and glutathionylation. Interestingly, we find palmitoylation of PLM is reduced in a mouse model of cardiac hypertrophy induced by ligation of the thoracic aorta, highlighting that the contribution of ion transporter palmitoylation to the development of cardiovascular diseases is a research area of considerable promise. We have recently undertaken proteomic profiling of protein palmitoylation in ventricular muscle. A considerable number of cardiac ion channels, transporters and ion transport regulators are palmitoylated, including NCX1 and the plasma membrane Ca ATPase PMCA1 (the two routes for Ca efflux during diastole), the Na pump catalytic α and regulatory β subunits, voltage gated Na channel pore-forming and regulatory subunits, and voltage gated Ca channel pore-forming and regulatory subunits. Although the sites and functional effects of palmitoylation of these transporters are still to be fully defined, it is strikingly significant that every route of entry and exit of Na and Ca into and out of cardiac myocytes is palmitoylated. Since palmitoylation may directly regulate spatial organisation as well as ion channel / transporter activity, the role of palmitoylation in the acute and long term co-ordination of cardiac sarcolemmal Na and Ca fluxes, and therefore excitation-contraction coupling and cardiac contractility may prove as significant as any post-translational modification investigated to date.