The study of the dissemination of the electrical impulse throughout the ventricular myocardium, which gave rise to the current theories, was carried out without taking into consideration the complex architecture of the cardiac muscle elucidated by more recent researchers. We propose a novel hypothesis based on the special macroscopic structure of the heart, the anisotropic electrical and mechanical behavior of the myocardium, the characteristics of the intercellular matrix and its very special collagen scaffolding, chemical composition, and biochemistry. The unique properties of the intercellular matrix would make it especially suited to function, in conjunction with the specialized conducting system (His-Purkinje system) as an efficient anisotropic conductor for the spread of electrical activation in the heart in order to allow an optimal sequence of excitation-contraction coupling that results in the coordination of effective myocardial contraction in birds and mammals of the most varied known heart rates. An analysis of certain clinical conditions that raise questions regarding current hypothesis and a review of novel techniques for recording transmembrane and extracellular potentials, which will provide a much firmer basis for the study of cardiac activation and the influence of myofiber architecture and which will allow in depth testing of hypotheses are presented.