Within the vasculature, specialized cellular extensions from endothelium (and sometimes smooth muscle) protrude through the extracellular matrix where they interact with the opposing cell type. These structures, termed myoendothelial junctions, have been cited as a possible key element in the control of several vascular physiologies and pathologies. This review will discuss observations that have led to a focus on the myoendothelial junction as a cellular integration point in the vasculature for both homeostatic and pathological conditions and as a possible independent signaling entity. We will also highlight the need for novel approaches to studying the myoendothelial junction in order to comprehend the cellular biology associated with this structure.