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The tight control of blood magnesium (Mg2+) levels is of central importance for numerous physiological processes. A persistent low Mg2+ status (hypomagnesemia) is associated with severe health risks and is involved in the pathogenesis of type 2 diabetes mellitus, osteoporosis, asthma, and heart and vascular diseases. The current view has expanded significantly as a result of the identification of novel genes and regulatory pathways involved in hypomagnesemic disorders. This review aims to give an up-to-date overview of transient receptor potential melastatin 6 (TRPM6) regulation and its role in the maintenance of Mg2+ homeostasis.The epithelial Mg2+ channel TRPM6 is considered to be the Mg2+ entry pathway in the distal convoluted tubule of the kidney, where it functions as gatekeeper for controlling the body's Mg2+ balance. Various factors and hormones contribute not only to the function, but also to the dysregulation of TRPM6, which has a substantial impact on renal Mg2+ handling. Recent genetic and molecular studies have further elucidated the signaling processes of epithelial Mg2+ transport, including their effect on the expression and function of TRPM6.Knowledge of TRPM6 functioning is of vital importance to decipher its role in Mg2+ handling and will, in particular, provide a molecular basis for achieving a better understanding of Mg2+ mal(re)absorption and hence systemic Mg2+ balance.