Recently published optical mapping studies of larger mammals, including humans, have identified functionally discrete sinoatrial exit pathways of activation. This is in line with earlier mapping studies of the dog and the human but in contrast with findings in the mouse and the rabbit, wherein a propagation wave front pattern of activation has been described. It underpins the complex three-dimensional (3D) organization of the cardiac pacemaking and conduction system in larger species, wherein sinoatrial and atrioventricular nodal physiologies both demonstrate identifiable activation pathways, which coincide with anatomic landmarks and histologic architecture, so that in addition to muscle fiber orientation and cell coupling, these intrinsic factors act to determine excitation pathways. This complex 3D organization increases the effect of source-to-sink mismatch both by greater variability in the space constant of tissue and by the 3D projection of this effect in all directions. Mathematical modeling provides a means to study these interactions, and newer models should incorporate these additional factors and their effect into the 3D structure of large mammal physiology.