Recently published optical mapping studies in larger mammals, including human, have identified functionally discrete sino-atrial exit pathways of activation. This is in line with earlier mapping studies in dog and human but in contrast with findings in mouse and rabbit, where a propagation wavefront pattern of activation has been described. It underpins the complex 3D organization of the cardiac pacemaking and conduction system in larger species, where sinoatrial and atrioventricular nodal physiology both demonstrate identifiable activation pathways, which coincide with anatomical landmarks and histological 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 of 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 in the 3D structure of large mammal physiology.