It was classically thought that the function of mammalian red blood cells (RBC) was limited to serving as a vehicle for oxygen, given the cell's abundance of cytosolic haemoglobin. Over the past decades, however, accumulating evidence indicates that RBC have the capacity to sense low oxygen tensions in hypoxic tissues, and subsequently release signalling molecules that influence the distribution of blood flow. The precise mechanisms that facilitate RBC modulation of blood flow are still being elucidated, although recent evidence indicates involvement of: i) adenosine triphosphate (ATP) - capable of binding to purinergic receptors located on the vascular wall prior to initiating nitric oxide (NO; a powerful vasodilator) production in endothelial cells, and/or ii) non-vascular NO - which is now known to have several modes of production within RBC, including an enzymatic process via a unique isoform of NO synthase (i.e., RBC-NOS), that has potential effects on the vascular smooth muscle. The physical properties of RBC - including their tendency to form three-dimensional structures in low shear flow (i.e., aggregation) and their capacity to elongate in high shear flow (i.e., deformability) - are only recently being viewed as mechanotransductive processes, with profound effects on vascular reactivity and tissue perfusion. Recent developments in intracellular signalling in RBC, and the subsequent effects on the mechanical properties of blood, and blood flow, thus present a vivid expansion on the classic perspective of these abundant cells.