MscS and MscL, bacterial mechanosensitive channels, play crucial roles in the hypo-osmotic shock response. However, only MscS has homologs in eukaryotes. These homologs are called MscS-like proteins or MSL proteins. MSL proteins have changed both structurally and functionally during evolution and are now localized not only to the membrane of the chloroplast, which is thought to be a descendant of an ancient, free-living bacterium, but also the cell membrane and the endoplasmic reticulum (ER) membrane, suggesting that the role of MSL proteins has diverged. In this brief review, we mainly focus on two MSL proteins in the fission yeast Schizosaccharomyces pombe that are localized in the ER membrane and protect cells from hypo-osmotic shock-induced death by regulating intracellular Ca(2+) concentrations. We also discuss Arabidopsis thaliana MSL proteins and other yeast ion channels in terms of osmoregulation in eukaryotes. 