Substantial advances have been made in characterizing the biophysical properties of channels formed exclusively by connexin isoforms expressed mainly in the heart, e.g., Cx43, Cx45 or Cx40. These properties include transjunctional and transmembrane voltage gating as well as their perm-selectivity, chemical gating and, at a single channel level, their multiple open states and changes in mode behavior. Nonetheless, these connexins are rarely expressed individually in a cell and the presence of functional channels constituted by distinct connexin isoforms is now suspected to be a norm. In fact, combinations of the connexins that form heteromeric channels have been described in some tissues, increasing the necessity to reinforce the research that leads to understanding the effects of these heteromeric interaction on the gating and conducting characteristics of the channels. Furthermore, protein-protein interaction studies will help to understand which connexin domains are involved in these interactions and how they affect the physiology of channels and their interaction with other biological and structural molecules in the cell. New information on the biophysical properties of heteromultimeric channels suggests that interaction between connexins and connexons is not as simple as once thought. Theoretically, changes in the coupling of homomeric connexons (Cx43) in the myocardium may not be significant enough to change the physiology of the heart or to incite arrhythmias, but when heteromeric channels are present, alteration in conductance, differential gating sensitivity to bio-gating molecules and changes in voltage sensitivity increase substantially the cell resources to modulate intercellular coupling, which may participate in the physiology and/or pathology of the cardiovascular tissues.