With their propensity to lead to sudden death, cardiac arrhythmias are a major clinical problem. They also represent an exciting medical challenge which needs gene-to-bedside studies to unravel the underlying arrhythmogenic mechanisms. Although rare, cardiac channelopathies have broadened our understanding of proarrhythmic mechanisms, as demonstrated with SCN5A-related arrhythmias. The SCN5A gene encodes the human cardiac voltage-gated sodium channel Nav1.5 (Rooket al., 2012). Representing the vast majority of the cardiac Na+ channels, Nav1.5 plays a key role in cardiac electrophysiology. Nav1.5 is involved in the initiation and conduction of action potentials. Mutations in Nav1.5 lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, isolated progressive cardiac conduction defect (Lenègre disease) and numerous overlap syndromes (Wilde & Brugada, 2011). For several years now, we have been interested in the study of SCN5A mutations trying to decipher the mechanisms linking the protein dysfunction and the disease, in order to unveil the role of Nav1.5 in myocardium electrical activity and structure. Although patch-clamp studies in heterologous expression systems have provided key information to understand the genotype-phenotype relationships of these diseases, they could not clarify how mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of them and for the overlapping syndromes. The use of mathematical models of action potentials has provided further information. Genetically modified mouse models turned out to be powerful tools to elucidate the pathophysiological mechanisms of SCN5A- and other gene-related arrhythmic diseases and offer the opportunity to investigate the cellular consequences of gene mutations such as the remodelling of other gene expression that might participate to the overall phenotype and explain some of the differences among patients (Derangeon M et al., 2012). Among these genes are those coding for Nav1.5 auxiliary subunits. Dozens of Nav1.5 auxiliary proteins have been described (Abriel, 2010). We identified and studied the function and potential role of one of them, 14-3-3 (Allouis et al., 2006). We are currently investigating its involvement in the regulation of Nav1.5 expression by the ubiquitin ligase Nedd4-2. Most recently, we linked a new pathological entity that we named MEPPC for multifocal ectopic Purkinje-related premature contractions, to a single SCN5A mutation (Laurent et al., 2012).