Palmitoylation (S-acylation) is the reversible conjugation of a fatty acid 
(usually C16 palmitate) to intracellular cysteine residues of proteins via a 
thioester linkage. Palmitoylation anchors intracellular regions of proteins to 
membranes because the palmitoylated cysteine is recruited to the lipid bilayer. 
NCX1 is palmitoylated at a single cysteine in its large regulatory intracellular 
loop. The presence of an amphipathic α-helix immediately adjacent to the NCX1 
palmitoylation site is required for NCX1 palmitoylation. The NCX1 palmitoylation 
site is conserved through most metazoan phlya. Although palmitoylation does not 
regulate the normal forward or reverse ion transport modes of NCX1, NCX1 
palmitoylation is required for its inactivation: sodium-dependent inactivation 
and inactivation by PIP2 depletion are significantly impaired for 
unpalmitoylatable NCX1. Here we review the role of palmitoylation in regulating 
NCX1 activity, and highlight future questions that must be addressed to fully 
understand the importance of this regulatory mechanism for sodium and calcium 
transport in cardiac muscle.