Blood flow control in the microcirculation requires coordinated interplay among the multiple branches of vascular resistance networks. These branches include arterioles embedded within the tissue parenchyma and their upstream feed arteries located external to the tissue. Vasoactive stimuli arising from cellular activity at discrete locations within a tissue (e.g., skeletal muscle fibres of motor units) activate receptors and ion channels of both smooth muscle cells and endothelial cells. The ensuing chemical and electrical signals must be integrated among vessel branches to effectively increase local perfusion in accord with local nutritive requirements of metabolic demand. Ascending vasodilatation is an intrinsic property of the resistance vasculature that enables signals initiated at discrete sites to spread from cell to cell along and among network branches. As demand (e.g., exercise intensity) increases, dilatation originating in distal arterioles governing capillary perfusion spreads upstream into intermediate and proximal arterioles that control the distribution and magnitude of tissue blood flow. Ascending dilatation of feed arteries coordinately governs total flow entering the microcirculation. The axial orientation of endothelial cells and their robust coupling to each other through gap junctions underscores the effectiveness of the endothelium as a cellular pathway for transmitting signals along vessel walls. In turn, heterocellular coupling through myoendothelial gap junctions enables radial signalling from the endothelium into consecutive smooth muscle cells to coordinate their relaxation and the spread of vasodilatation. Through altering cell-to-cell coupling, the regulation of gap junction expression and patency (e.g., by phosphorylation, nitrosylation and accessory proteins) can modulate both longitudinal and radial signalling in resistance networks. Intercellular signalling is also modulated by ion channels in plasma membranes. For example, the fall in membrane resistance upon activating small- and intermediate- Ca2+ activated K+ channels (SK/IK) along the endothelium promotes the dissipation of electrical signals, thereby “tuning” the effective distance of transmission. Inherent to myoendothelial coupling is that variations in the size, number and functional channels of smooth muscle cells further modulate longitudinal signalling. In addition to their intimate coupling to the endothelium, smooth muscle cells throughout resistance networks are enmeshed by a plexus of perivascular nerves coursing along the adventitia. Upon physical stress, increased sympathetic nerve activity promotes vasoconstriction that competes against vasodilator signals arising from both skeletal muscle and endothelium. In turn, the activation of adrenergic receptors on smooth muscle cells generates second messengers (e.g., inositol trisphosphate and Ca2+) that can diffuse through myoendothelial gap junctions to signal endothelial cells reciprocally. Independent of autacoid production, the opening of SK/IK (i.e., endothelium-dependent hyperpolarization) can thereby modulate vasoconstriction along the network while attenuating the efficacy of electrical conduction. Thus, irrespective of gap junctions, regulating ion channels in plasma membranes can govern local perfusion by modulating ascending vasodilatation. Such dynamic interactions between parenchymal cells, vascular cells and perivascular nerves effectively coordinate vasomotor activity throughout resistance networks to ensure perfusion according to local needs. Vasodilatation predominates in distal and intermediate arterioles, where sympathetic vasoconstriction is overridden as metabolic demand increases (i.e., “functional sympatholysis”). At the same time, resistance is maintained in proximal arterioles and feed arteries, where sympathetic neuroeffector signalling suppresses ascending vasodilatation via complementary actions on both smooth muscle and endothelium. While restricting dilatation of proximal vessels limits maximal tissue perfusion, the negative modulation of ascending vasodilatation maintains peripheral resistance and arterial perfusion pressure. In doing so, the integration of intercellular signalling underlying blood flow control ensures the ability to support the elevated demands of intense physical activity. Ongoing investigations focus on understanding how such key signalling events are altered by aging and disease.