Our understanding of the molecular mechanisms of renal magnesium (Mg2+) handling has greatly enhanced over recent years. This review highlights the regulatory factors controlling Mg2+ homeostasis through its effects on the epithelial Mg2+ channel TRPM6 (Transient Receptor Potential Melastatin subtype 6), the gatekeeper of the body's Mg2+ balance. Drug treatment, acid-base status, and several hormones have been shown to regulate TRPM6 expression, while its channel activity is modified by intracellular Mg2+, pH, and ATP. Recently, epidermal growth factor (EGF) and estrogen have been implicated as magnesiotropic hormones. The stimulation of the EGF receptor (EGFR) leads to an intracellular cascade involving Rac1 that promotes trafficking of TRPM6 to the plasma membrane. Furthermore, long-term EGF treatment upregulates the expression of TRPM6. Estrogen has also been shown to stimulate TRPM6 activity upon short-term treatment, next to its long-term regulatory effect on TRPM6 transcription. TRPM6, and its closest homologue TRPM7, are composed of a Mg2+ -permeable channel fused to an alpha-kinase domain. In the intracellular compartment, the receptor for activated C-kinase (RACK1), the repressor for estrogen receptor activity (REA), and ATP were identified as negative modulators of TRPM6 activity through its alpha-kinase domain. Therefore, the a-kinase domain acts as an indirect player involved in Mg2+ homeostasis by its feedback function in the TRPM6-mediated Mg2+ influx.