A recent study in Science reveals that equilibrative nucleoside transporter 3 (ENT3) is essential for both lysosomal function and macrophage homeostasis. Similarly to patients with lysosomal storage disease owing to ENT3 mutations, ENT3-deficient mice were found to develop splenomegaly as a result of increased macrophage proliferation (histiocytosis). In the absence of functional ENT3, nucleosides accumulated in the lysosomes, leading to lysosomal alkalization. This, in turn, compromised lysosomal function, as indicated by a delay in the degradation of apoptotic cells and live bacteria by ENT3-deficient macrophages. Furthermore, the lysosomal degradation of the macrophage colony-stimulating factor 1 (CSF1)–CSF1 receptor complex was impaired in ENT3-deficient macrophages, resulting in persistent CSF1-mediated signalling, which was suggested to underlie the increase in macrophage proliferation. These findings suggest a link between lysosomal storage disease and macrophage histiocytosis.