Cell-cell signalling via Notch regulates multiple cell behaviours during development, and inappropriate Notch activation is a hallmark of many cancers. Consequently, it is important to understand exactly how Notch signalling is regulated. Thomas Vaccari and co-workers bring this goal a step closer on p. 1825 by reporting that the vacuolar ATPase (V-ATPase) proton pump, which acidifies endosomal compartments, is required for physiological and pathological Notch receptor activation in Drosophila. Once it is ligand bound, Notch is activated by γ-secretase-mediated cleavage, but mounting evidence suggests that Notch's entry into endosomes promotes its signalling. In a search for factors that regulate Notch activation in endosomes, the researchers isolated mutants in the Drosophila genes that encode V-ATPase subunits. Their characterisation of these mutants indicates that V-ATPase, probably via the acidification of early endosomes, promotes not only the lysosomal degradation of Notch to prevent excess signalling, but also the endosomal activation of Notch signalling. Thus, it might be possible to curtail Notch overactivation in tumours using V-ATPase inhibitors.