Founder populations, characterized by a single ancestor affected by LQTS and by a large number of individuals and families all related to the ancestor and thereby carrying the same disease-causing mutation, represent the ideal human model to study the role of “modifier genes” in the long QT syndrome (LQTS). This chapter reviews some of the fundamental concepts related to founder populations and provides the necessary historic background to understand why so many can be found in South Africa. The focus then moves onto a specific LQT1 founder population, carrier of the A341V mutation, that has been extensively studied during the last 10 years and has provided a significant number of previously unforeseen information. These novel findings range from an unusually high clinical severity not explained by the electrophysiological characteristics of the mutation, to the importance of the tonic and reflex control of heart rate for risk stratification, to the identification of the first modifier genes for the clinical severity of LQTS.