Extracellular ATP regulates biological processes throughout the nervous, immune and circulatory systems. Its effects are mediated by P2 purinergic receptors in the plasma membrane, including the P2X4 receptor, a ligand-gated ion channel. On p. 3838, Ruth Murrell-Lagnado and colleagues report that lysosomal sequestration and exocytosis regulate this receptor. They show that endogenous P2X4 receptors in rat microglia, endothelial cells and macrophages localize mainly to lysosomes. A dileucine motif and a tyrosine-based endocytic motif control lysosomal targeting, the authors report, and N-linked glycans protect the receptors from degradation once they arrive in lysosomes. The authors also show that, during phagocytosis, P2X4 receptors accumulate in the phagosome membrane, which suggests a function for them in intracellular membranes. By contrast, after stimulation of lysosomal exocytosis, the receptors (and the lysosomal marker LAMP-1) return to the cell surface and stimulate P2X4-mediated currents across the plasma membrane. Thus, the authors conclude, lysosome-resident P2X4 receptors provide a pool of functional receptors that can be mobilized to upregulate cellular responsiveness to extracellular ATP.