PI(3,5)P2 is a low abundant phospholipid synthesized by the lipid kinase PIKfyve and found in the membrane of late endosomes and lysosomes. Following pharmacological inhibiton of PIKfyve, PI(3,5)P2 depletion quickly and drastically impairs late endosomal/lysosomal formation, leading to the generation of big vacuoles. In a recent study, Gayle et al. observed that the deletion of ClC-7, a lysosomal transporter thought to facilitate lysosomal acidification, abolished the effects of PIKfyve inhibition, including vacuole formation (Gayle et al., Blood, 2017). In this new study, we are investigating the interplay between PIKfyve/PI(3,5)P2 and ClC-7 in lysosomal acidification and vacuole formation.