Magnesium is an important, predominantly intracellular cation that is required for a wide variety of cellular processes. The mammalian kidney plays a key role in whole-body magnesium homeostasis, but the molecular and cellular mechanisms that underlie renal epithelial magnesium reabsorption are poorly understood. Traditional physiologic approaches have been severely hampered by the lack of a useful radioisotope of magnesium that can be used for tracer flux studies. The present review discusses physiologic insights gained from recent reverse-genetic studies that have identified a plethora of genes involved in inherited renal magnesium wasting syndromes.