Chronic acidosis has previously been shown to induce an increase in acid-secreting α-intercalated cells and a decrease in HCO3-secreting β-intercalated cells in the cortical collecting duct (CCD), resulting in a net increase in CCD acid secretion. Now, Schwartz et al. report that the principal cells of the CCD are the sensors of acid levels. Using isolated CCDs, transgenic mice and cultured principal cells, they showed that these cells respond to acid by upregulating stromal cell-derived factor 1, which induces the change in intercalated cell subtype distribution that occurs in response to chronic acidosis.