We have shown earlier that in contrast to the traditional view of two-compartment osmotic equilibrium, large amounts of Na⁺ can be accumulated in the body without commensurate water retention. Na⁺ is stored in a third compartment, associated with increased glycosaminoglycan charge density in the skin. This third compartment is tightly regulated and features osmolality higher than in circulating plasma. Going beyond the physiological concept that body fluids are always at equilibrium, we have identified novel extrarenal regulatory mechanisms to mobilize interstitial electrolytes into the blood stream. It has be shown that local osmotic differences can be detected by tonicity enhancer binding protein (TonEBP), a transcription factor in macrophages. These macrophages then produce vascular endothelial growth factor (VEGF) C that regulates the lymphatic microenvironment and thereby this third compartment. This new concept suggests that macrophages are extrarenal regulators of electrolyte, volume, and blood pressure homeostasis via a novel regulatory feed-back control system. Our findings are apart from the traditional view of long-term Na⁺ balance and overall osmoregulation. However, they could usher in new concepts regarding heart failure, renal insufciency, and essential hypertension, all of which feature perturbed total body Na⁺ and water balance. Further studies to explore cells and molecules critically involved in this novel component of volume and blood pressure homeostasis may allow us to identify new targets for blood pressure control in patients with hypertension. In addition, this new area of research will usher in a new direction in patient-oriented hypertension research. To achieve this goal, interdisciplinary research approaches placed at the junction between medicine, biology, chemistry, and physics are needed to better understand the chemical biology involved in the maintenance of the internal environment.