Mg²⁺ influx across the luminal membrane is mediated by TRPM6 and may require the ubiquitous TRPM7. In this issue of the JCI, Groenestege et al. (11) report that EGF is a magnesiotropic hormone that regulates renal Mg²⁺ reabsorption by stimulating the EGFR, which then increases the activity of TRPM6. Aberrant targeting of pro-EGF to the basolateral membrane by the P1070L mutation results in reduced EGF production at the basolateral membrane, reduced activation of EGFR, reduced TRPM6 activity, and, consequently, Mg²⁺ wasting. Future studies should reveal which of the pathways activated by EGF mediates activation of TRPM6 and the mechanism by which TRPM6 activity is increased. As indicated by the long arrows, activation of EGFR by EGF and its tyrosine phosphorylation may directly activate TRPM6 and/or TRPM7 channel activity or may regulate insertion or retrieval or TRPM6 present in intracellular vesicular compartments. Because of the proximity of the DCT and proximal tubule, EGF generated by the DCT may activate EGFRs at the proximal tubule and therefore affect Mg²⁺ handling by this nephron segment, which reabsorbs 25% of filtered Mg²⁺. DAG, diacylglycerol; IP₃, inositol-1,4,5 trisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PLCγ, phospholipase Cγ; P, phosphate.