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and functions of animal cells under physiological and pathological conditions. Two types of chloride channels are directly activated by cell swelling and involved in CVR. One is the volume-sensitive outwardly rectifying anion channel (VSOR) [1], also called the volume-regulated anion channel (VRAC) [2], which is ubiquitously expressed and exhibits the phenotypic properties [1, 2]; and another is the maxi-anion channel (Maxi-Cl), the core component of which has recently been identified as SLCO2A1 [3]. As to the molecular identity of VSOR/VRAC (simply called VSOR hereafter), the first breakthrough was brought about by the discovery of involvements of LRRC8 members [4, 5]. In this issue of Experimental Neurobiology, Han et al. [6] makes the second breakthrough by demonstrating the involvement of Tweety homologs (TTYH) in the VSOR channel activity. Two groups [7, 8] independently discovered the existence of functional VSOR in 1988. Since then, for a quarter of a century, its molecular identity had not been uncovered, despite much efforts of proposing and disproving many false-positive candidates, as summarized recently [9]. In 2014, two groups [4, 5] independently identified LRRC8A or SWELL1 as one of essential components of VSOR channel and reported on the same day. In addition, LRRC8C, 8D or 8E was later found to be required together with LRRC8A for functional VSOR activity [5, 10, 11]. The pore-forming roles of these LRRC8 members were suggested by discernible, though not drastic, alterations of ion selectivity by some point mutations and evidenced by successful reconstitution of anionic channel activity as well as by recent cryo-EM structure studies with purified LRRC8s, as summarized recently [12, 13]. However, it must be pointed out that several important properties (such as their cytoplasmic ATP independence, smaller single-channel conductance, and little voltage-dependent inactivation kinetics) of LRRC8-reconstituted channels are distinct from those of native VSOR channel, as summarized recently [9, 14]. More importantly, the channel reconstituted with purified LRRC8A plus 8D or 8E was activated by reduction of ionic strength (Γ), but not by inflation-induced membrane expansion [15]. In addition, a reduced cytoplasmic Γ was found to be required to activate the channels in HEK293 cells expressing LRRC8A alone or LRRC8A plus 8C [16]. In contrast, native VSOR channels can be activated by cell swelling-associated expansion of membrane infoldings [1] and inflation or membrane expansion by forcing fluid into the cells without any Γ reduction [17] (also see [12]). Thus, it is highly likely that the LRRC8 channel is not the membrane expansion-activated volume-regulatory anion channel (Me-VRAC or VRACswell [6]), but the ionic strength-sensitive volume-regulatory anion channel (Is-VRAC or VRACΓ [6]). On the other hand, it is also evident that LRRC8 members play some roles in swelling-induced activation of anion channel currents exhibiting VSOR phenotypes, because swelling-activated VSOR currents were never observed in cells lacking all five LRRC8 genes but rescued by expressing LRRC8A together with LRRC8C or 8E [5], and because coinjection of LRRC8A RNA together with LRRC8D or 8E RNA gave rise to hypotonicity-induced VSOR currents in Xenopus oocytes which lack all LRRC8 genes and endogenous VSOR activity [18]. However, it Tweety Homologs (TTYH) Freshly Join the Journey of Molecular Identification of the VRAC/VSOR Channel Pore