The ability of cells to regulate their volume when exposed to anisotonic environments is important for cellular homeostasis. Hypotonic environments cause cells to swell through osmosis but many vertebrate cells quickly shrink back to normal by what is known as regulatory volume decrease (RVD). Marina Jendrach and co-workers now report that TRPV4, a member of the vanilloid subfamily of transient-receptor-potential channels, directly participates in RVD (see p. 2435). They show that RVD in HaCaT cells, a TRPV4-expressing human keratinocyte cell line, involves a significant Ca2+ influx. Both RVD and the Ca2+ influx are blocked by Gd3+, which inhibits TRPV4. Then, the authors express a TRPV4-EGFP fusion protein in CHO cells, which do not normally express TRPV4 or undergo RVD under hypotonic conditions. These engineered cells undergo RVD after a Ca2+ influx, and this is reduced by Gd3+. Together, these results suggest a model in which cellular swelling caused by osmosis increases tension in the cell membrane and activates TRPV4; this mediates a Ca2+ influx, which activates the signalling cascades that lead to RVD.