Direct cell-to-cell communication through specialized intercellular channels is a characteristic feature of virtually all multi-cellular organisms. The remarkable functional conservation of cell-to-cell coupling throughout the animal kingdom, however, is not matched at the molecular level of the structural protein components. Thus protostomes (including nematodes and flies) and deuterostomes (including all vertebrates) utilize two unrelated families of gap-junction genes, innexins and connexins, respectively. The recent discovery that pannexins, a novel group of proteins expressed by several organisms, are able to form intercellular channels has started a quest to understand their evolutionary relationship and functional contribution to cell communication in vivo. There are three pannexin genes in mammals, two of which are co-expressed in the developing and adult brain. Of note, pannexin1 can also form Ca2+-activated hemichannels that open at physiological extracellular Ca2+ concentrations and exhibit distinct pharmacological properties.