In 1997, the Committee for Proprietary Medicinal Products (CPMP) issued a document concerning the potential of non-cardiovascular drugs to cause prolongation of the QT interval of the electrocardiogram. This article reviews several aspects of this complex problem, including a preclinical strategy (in vitro electrophysiology in human cardiac cells and in vivo pharmacologically validated conscious dogs) to satisfy the expectations of the CPMP. In particular, the discussion stresses the danger of drugs prolonging the QT interval in patients with concurrent cardiac risk factors and the need for rigorous clinical testing to determine the risk of fatal cardiac events for drugs with the propensity to prolong QT.