Sodium channel dysfunction causes cardiac conduction disturbances, ventricular arrhythmias, and sudden death, both during common pathological conditions such as myocardial ischemia and heart failure, and in the setting of inherited mutations in the SCN5A gene encoding the cardiac sodium channel. Mutations in SCN5A are associated with a broad spectrum of cardiac rhythm disorders (1). Gain-of-function mutations prolong cardiomyocyte repolarization and cause the Long-QT syndrome (type 3, LQT3), which manifests with QT-interval prolongation on the ECG. Loss-of-function mutations reduce the action potential upstroke velocity and cause Cardiac Conduction Disease (CCD), associated with prolonged conduction indices (PR interval, QRS duration) on the ECG, occurring either in isolation or in combination with ST-segment elevation in the right precordial ECG leads (Brugada syndrome, BrS). In some instances, SCN5A mutations are associated with multiple sodium channel biophysical defects and lead to clinical manifestations of both gain (LQT3) as well as loss (CCD, BrS) of sodium channel function. The first such “overlap” mutation, SCN5A-1795insD, was described by our group in a large Dutch family with clinical manifestations of LQT3, BrS and CCD occurring either in isolation or in combinations thereof (2). Knock-in mice (Scn5a1798insD/+) carrying the mouse homolog of this mutation recapitulated the diverse clinical features observed in patients and provided insight into the distinct sodium channel biophysical defects underlying the different disease manifestations (3). More recently, sodium channelopathies have also been associated with the development of cardiac fibrosis, dilatation and hypertrophy, conditions which may further contribute to arrhythmogenesis (4). These observations have led to the re-evaluation of the initial view that mutations in a cardiac ion channel would only lead to pure electrical dysfunction and imply a functional role as signal transducer for the sodium channel, regulating myocyte structural integrity and viability. However, the underlying mechanisms involved are not completely known, and it remains unclear how the sodium channel regulates cardiomyocyte integrity and viability. Sodium channelopathies are also characterized by reduced penetrance and variable disease expression, with extensive variability in clinical manifestations often observed even among family members carrying an identical ion channel gene mutation. We have demonstrated a greater severity of conduction and repolarization disease in Scn5a1798insD/+ mice of the 129P2 inbred strain, as compared to the FVB/N inbred genetic background, attesting to the important role for genetic background in modulation of disease severity in cardiac sodium channelopathy (5,6). However, genetic modifiers of phenotypic variability in patients with arrhythmia syndromes remain largely unknown. Identification of these modifiers represents an exciting next major step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification, and treatment strategies.