We used microarray analysis to identify renal cell transcripts that were upregulated with low magnesium. One transcript, identified as NIPA2 (nonimprinted in Prader-Willi/Angelman syndrome) subtype 2, was increased over 2-fold relative to cells cultured in normal magnesium. The deduced sequence comprises 129 amino acids with 8 predicted transmembrane regions. As the secondary structure of NIPA2 conformed to a membrane transport protein, we expressed it in Xenopus oocytes and determined that it mediated Mg²uptake with two-electrode voltage-clamp and fluorescence studies. Mg²⁺ transport was electrogenic, voltage-dependent and saturable, demonstrating a Michaelis affinity constant (K_m) of 0.31 mM. Unlike other reported Mg²⁺ transporters, NIPA2 was very selective for the Mg²⁺ cation. NIPA2 mRNA is found in many tissues but particularly abundant in renal cells. Using immunofluorescence, it was shown that NIPA2 protein was normally localized to the early endosomes and plasma membrane and was recruited to the plasma membrane in response to low extracellular magnesium. We conclude that NIPA2 plays a role in magnesium metabolism and regulation of renal magnesium conservation.