Gap junctions are essential for intercellular crosstalk in blood and lymphatic vasculature. These clusters of intercellular channels ensure direct communication among endothelial cells and between endothelial and smooth muscle cells, and the synchronization of their behavior along the vascular tree. Gap junction channels are formed by connexins; six connexins form a connexon or hemichannel and the docking of two connexons result in a full gap junction channel allowing for the exchange of ions and small metabolites between neighboring cells. Recent evidence indicates that the intracellular domains of connexins may also function as an interaction platform (interactome) for other proteins, thereby regulating their function. Interestingly, fragments of Cx proteins generated by alternative internal translation were recently described, although their functions in the vascular wall remain to be uncovered. Variations in connexin expression are observed along different types of blood and lymphatic vessels; the most commonly found endothelial connexins are Cx37, Cx40, Cx43 and Cx47. Physiological studies on connexin-knockout mice demonstrated the essential roles of these channel-forming proteins in the coordination of vasomotor activity, endothelial permeability and inflammation, angiogenesis and in the maintenance of fluid balance in the body.