Gap junctional channels are a class of membrane channels composed of transmembrane channel-forming integral membrane proteins termed connexins, innexins or pannexins that mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. The activity of these channels is tightly regulated, particularly by intramolecular modifications as phosphorylations of proteins and via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signaling enzymes, substrates, and potential effectors (such as channels) into multiprotein signaling complexes that may be anchored to the cytoskeleton. Protein-protein interactions play essential roles in channel localization and activity and, besides their cell-to-cell channel-forming functions, gap junctional proteins now appear involved in different cellular functions (e.g. transcriptional and cytoskeletal regulations). The present review summarizes the recent progress regarding the proteins capable of interacting with junctional proteins and highlights the function of these protein-protein interactions in cell physiology and aberrant function in diseases. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.