An interpretative synthesis of all factors that have been shown to influence erythrocyte deformability and aggregation leads to postulate several regulatory axes in which blood rheology appears to be involved. One important regulatory loop involves 'viscoregulation' by erythropoietin, which governs the balance between red cell mass and blood fluidity and is a regulator of metabolism. Erythrocytes are also local regulators of water osmolality via the water-conducting channel aquaporin-1, so that when hyper or hypo-osmolality appears in a microvascular segment, red cell transit velocity decreases as a consequence of increased RBC rigidity, allowing this AQP1-driven exchange to completely restore iso-osmolality. Erythrocyte energy status is a major determinant of their rheologic properties, involving the release of ADP and ATP. Increasing values of glucose, cholesterol and triglycerides are associated with a decrease in red cell deformability while hormones regulating the flux of those substrates rather improve red cell rheology. Increase in circulating levels of GH and IGF1 are reported to be associated with moderately increased red cell rigidity and aggregation, while IGFBP1 may improve viscosity factors, modulating tissue supply of substrates needed for anabolism. An effect of sex hormones on red cell rheology may be involved in the regulation of fertility. Catecholamines also regulate during stress RBC rheology via α-and β-adrenergic receptors. This novel property of the red cell is thus another homeostatic loop involving red cell rheology.