Cardiac arrhythmias comprise a group of syndromes with various clinical outcomes, the most severe of which are life-threatening arrhythmias and sudden cardiac death. Although numerous mutations in the genes encoding for cardiac ion channels have been identified as an underlying cause of cardiac arrhythmias, the anticipated revolution in terms of personalized risk stratification and clinical management has not been achieved. A major hurdle remains in the poor correlation between the genetic profile and clinical manifestations, the cause of which remains largely unknown. As a consequence, with our present mechanistic understanding of inherited arrhythmias and the treatment thereof, affected individuals are at risk of receiving inappropriate clinical management and remain at risk of suffering sudden cardiac death. This project utilizes diverse approaches such as electrophysiology, molecular dynamics simulations, and synthetic chemistry to explore innovative approaches to personalized risk stratification and novel concepts for drug design. One important aspect of this proposal is the systematic mapping of major endogenous ligands with therapeutic or pathological effects on cardiac ion channels, which we refer to as resilience and trigger factors, and how these factors are tied to major classes of inherited mutations. Another important aspect of this proposal is the fundamentally novel concept of Resilience-Mimetic Drug development, which utilizes and tweaks the effect of resilience factors on cardiac ion channels. Hence, the overall objective is to provide a molecular framework for how major arrhythmia factors determine arrhythmia severity in a predictable and mutation-specific manner, and to utilize these mechanistic insights to develop a fundamentally novel concept of anti-arrhythmic treatment. Ultimately, future personalized risk stratification and clinical management will improve the clinical outcome for individuals who suffer from inherited arrhythmias.