Patch-clamp studies of anion channels show a bewildering variety in their properties and regulation mechanisms. Amongst them, the anion channels activated by hypo-osmotic cell swelling (ICl,swell) have drawn attention because of their wide expression in virtually every vertebrate cell(s), including cardiac myocytes, and their critical roles in cell volume regulation.2–4 Cells need to regulate their volume in the face of several external and internal challenges. For this purpose, cells are endowed with various ion channels and transporters that become activated upon cell swelling or shrinkage. ICl,swell are also called by different names like volume-regulated anion channels and volume-stimulated osmolyte and anion channels, implicating their permeability to a wide variety of anionic molecules including organic substances and ATP. In spite of their importance and ubiquitous expression, their molecular nature is still the subject of controversy and remains unclear. One of the key issues in ICl,swell is the activation mechanism, i.e. how is the hypo-osmotic stress transduced into anion channel activation? A direct mechanical gating is unlikely with regard to the considerable time lag between hypotonic challenge and steady-state activation of ICl,swell. The list of suggested mechanisms or critical factors supported by experimental evidence include reduced ionic activity, G protein activation, lipoxygenase metabolites, MAP kinase and tyrosine kinase pathways, and reactive oxygen species generated from NADPH oxidase (NOX). Such a perplexing picture definitely indicates that multiple mechanisms are involved and knotted to activate ICl,swell , depending on the tissue and cell types.