The sudden unexplained death syndrome, a tragic and devastating event, is often the result of cardiac arrhythmias associated with defects in ion channels. Autopsies are unrevealing due to the absence of an obvious cardiac pathology in these disorders. Substantial efforts have been devoted to identify genetic variations known to cause long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia, all of which have been wellrecognized for their risk of sudden death. Genetic polymorphisms in the ion channel genes under study have also been known to modulate the response to drugs and predispose susceptible individuals to life-threatening arrhythmias. Cardiotoxicity is a serious adverse effect which limits the therapeutic potential of a vast number of clinically available drugs. The awareness of putative drug-gene interactions may lead to the tailoring of therapy for the individual patient based on genetic make-up, as well as the molecular design of drug molecules with reduced cardiac side effects. These efforts aim to prevent the occurrence of sudden unexpected deaths, or adverse complications from drugs. This expert review outlines the emerging strategies to move beyond the idiopathic occurrence of the sudden death syndrome, through a consideration of the molecular genetic pathogenesis of non-ischaemic cardiac conditions underpinning sudden death. Additionally, we discuss the results of our ongoing original research and mutation screening efforts to identify genetic biomarkers for the sudden unexplained death syndrome.