The ability to control the cellular content of ions and organic osmolytes and hence to restore cell volume following osmotic perturbation is pivotal for cell function. The intracellular signaling events evoked by cell swelling /cell shrinkage and leading to restoration of cell volume as well the biophysical and pharmacological characteristics of volume sensitive transporters for osmolytes have recently been reviewed (1-3). Osmotic cell swelling is in several cell lines, e.g., NIH3T3 mouse fibroblasts, porcine myotubes, HTC cells (liver-derived cell line) and neonatal rat cardiomyocytes accompanied by an increase in the production of reactive oxygen species (ROS). The constitutively active NOX4/p22phox complex constitutes the catalytic core of the volume sensitive NADPH oxidase in the NIH3T3 fibroblasts and it has been shown that lysophosphatidic acid (LPA) and protein kinase C (PKC)potentiate NOX4 activity under hypotonic conditions(4). Cell swelling also provokes activation of phospholipase A2 (PLA2) activity in NIH3T3 cells and as stimulation of the ROS production in NIH3T3 cells occurs down-stream to the PLA2 activation it seems plausible that PLA2- generated LPA could account for the potentiation of NADPH oxidase activity following cell swelling. ROS favor net loss of osmolytes, i.e, the organic osmolyte taurine as well as ions (5), whereas NOX4 knock-down (siRNA) impairs the swelling-induced increase in the ROS production as well as taurine release in NIH3T3 fibroblasts. Thus, the volume sensitive NOX4/p22phox complex is essential for modulation of the swelling-induced increase in ROS production and the concomitant potentiation of volume-sensitive taurine release in NIH3T3 fibroblasts. 1. Hoffmann, Lambert, Pedersen, Physiological Reviews 89, p193 (2009). 2. Lambert, Neurochem. Res. 29, p27 (2004). 3. Lambert, Hoffmann,Pedersen, Acta Physiol Scand. 194, p255 (2008). 4. Friis,Vorum, Lambert, Am. J. Physiol Cell Physiol 294, C1552 (2008). 5. Lambert,Klausen,Bergdahl,Hougaard,Hoffmann. Am.J.Physiol Cell Physiol 297, C198-C206. 6-5- 2009.