The volume-sensitive outwardly rectifying or volume-regulated anion channel, VSOR/VRAC, which was discovered in 1988, is expressed in most vertebrate cell types, and is essentially involved in cell volume regulation after swelling and in the induction of cell death. This series of review articles describes what is already known and what remains to be uncovered about the functional and molecular properties as well as the physiological and pathophysiological roles of VSOR/VRAC. This Part 2 review article describes, from the physiological and pathophysiological standpoints, first the pivotal roles of VSOR/VRAC in the release of autocrine/paracrine organic signal molecules, such as glutamate, ATP, glutathione, cGAMP, and itaconate, as well as second the swelling-independent and -dependent activation mechanisms of VSOR/VRAC. Since the pore size of VSOR/VRAC has now well been evaluated by electrophysiological and 3D-structural methods, the signal-releasing activity of VSOR/VRAC is here discussed by comparing the molecular sizes of these organic signals to the channel pore size. Swelling-independent activation mechanisms include a physicochemical one caused by the reduction of intracellular ionic strength and a biochemical one caused by oxidation due to stimulation by receptor agonists or apoptosis inducers. Because some organic substances released via VSOR/VRAC upon cell swelling can trigger or augment VSOR/VRAC activation in an autocrine fashion, swelling-dependent activation mechanisms are to be divided into two phases: the first phase induced by cell swelling per se and the second phase caused by receptor stimulation by released organic signals.