A major goal of this work is to demonstrate the relationship of the electrocardiographic waveform to the transmembrane action potential that is generated by the movement of ions across the cell membrane via various ionic channels and ionic pumps from the extracellular space to the intracellular space and vice-versa. Changes in extracellular and intracellular ionic concentrations, drugs which affect the ionic channels and ionic pumps, i.e. cardioactive drugs such as the antiarrhythmic agents, and pathological changes such as those associated with myocardial ischemia will influence the movement of ions, particularly sodium, potassium and calcium across the cell membrane and this will result in changes in the transmembrane action potential. These action potential changes will be mirrored by changes in the electrocardiographic waveform. The relationship between the ECG and the action potential is such that it is possible to predict the changes in the electrocardiographic waveform that will accompany changes in the action potential and conversely, to predict the changes in the action potential that underlie changes in the electrocardiogram. In this chapter, we will review the ionic events responsible for the action potential, discuss the changes in the action potential caused by changes in extracellular ionic concentrations, particularly potassium and calcium and show how these changes are mirrored by changes in the electrocardiogram. We will discuss the mechanism by which cardioactive drugs influence ionic fluxes to change the action potential and how these changes may actually potentiate the development of arrhythmias. We will then discuss the congenital long QT Syndromes in which genetic modifications of the sodium and potassium channels cause changes in the action potential which result in lengthening of the QT interval on the electrocardiogram and form the substrate for a unique form of life threatening ventricular tachycardia known as Torsade de Pointes. The final section focuses on the Brugada syndrome, a genetically mediated disorder that is also associated with life threatening ventricular arrhythmias.