This article examines the central role of Na,K‐ATPase (α1β1FXYD2) in renal Mg handling, especially in distal convoluted tubule (DCT), the segment responsible for final regulation of Mg balance. By considering effects of Na,K‐ATPase on intracellular Na and K concentrations, and driving forces for Mg transport, we propose a consistent rationale explaining basal Mg reabsorption in DCT and altered Mg reabsorption in some human diseases. FXYD2 (γ subunit) is a regulatory subunit that adapts functional properties of Na,K‐ATPase to cellular requirements. Mutations in FXYD2 (G41R), and transcription factors (HNF‐1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K‐ATPase. Renal Mg wasting implies that Na,K‐ATPase is inhibited, but in vitro studies show that FXYD2 itself inhibits Na,K‐ATPase activity, raising K_0.5Na. However, FXYD2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane. Renal Mg wasting associated with impaired Na,K‐ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K‐ATPase. We consider also the role of the Na,K‐ATPase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension (FHHt). Renal Mg handling serves as a convenient marker for Na,K‐ATPase activity in DCT.