Drug induced cardiac arrhythmia, especially occurrence of Torsade de Pointes (TdP), has been a leading cause of attrition and post-approval re-labelling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. A drug that is well tolerated in most patients can cause TdP in a particular individual under certain clinical situations e.g. co-medications or electrolyte imbalance. Moreover, assessment of the TdP liability of a drug based only on the parent moiety and the hERG centric evaluations could be misleading. Testing all probable hypotheses in clinical and/or animal studies may be practically, ethically and economically unfeasible. These present a translational gap in extrapolating preclinical cardiac safety assessment to estimate human TdP risk reliably. As part of this thesis, it was demonstrated with case examples how mechanistic approach such as Quantitative Systems Toxicology and Safety (QSTS) an be used from early discovery to late stage drug development and post marketing surveillance safety assessment where the model can be further verified, refined and enriched by “predict-learn-confirm” process as more in vitro and clinical data becomes available. Adoption of such QSTS modelling strategies can significantly benefit precise TdP risk assessment and mitigation.