Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. Previous research has outlined that NET activity and trafficking is modulated via reversible post-translational modifications like phosphorylation and ubiquitylation. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is another post-translational modification responsible for numerous biological mechanisms. In this study, we reveal that NET is dynamically palmitoylated and inhibition of this modification with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP), results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely with a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted WT hNET palmitoylation and elevated NET protein levels. The POTS associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable fragments. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of POTS.