Thanks to the contribution of molecular genetics, the genetic bases, the pathogenesis and genotype-phenotype correlation of diseases such as the Long QT syndrome, the Brugada Syndrome, the Progressive cardiac conduction defect (Lenegre disease), the Catecholaminergic Polymorphic Ventricular Tachycardia and Andersen Syndrome have been progressively unveiled and show an extremely high degree of genetic heterogeneity. The evidences supporting this concept are outlined with a particular emphasis on the growing complexity of the molecular pathways that may lead to arrhythmias and sudden death, in term of the relationships between genetic defect(s) and genotype(s) as well as gene-to gene interactions. The current knowledge is reviewed, focusing on the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways.