| Summary: | Magnesium (Mg) is the second most abundant cation in mammalian cells, and it is essential for numerous cellular processes including enzymatic reactions, ion channel functions, metabolic cycles, cellular signaling, and DNA/RNA stabilities. Because of the versatile and universal nature of Mg<sup>2+</sup>, the homeostasis of intracellular Mg<sup>2+</sup> is physiologically linked to growth, proliferation, differentiation, energy metabolism, and death of cells. On the cellular and tissue levels, maintaining Mg<sup>2+</sup> within optimal levels according to the biological context, such as cell types, developmental stages, extracellular environments, and pathophysiological conditions, is crucial for development, normal functions, and diseases. Hence, Mg<sup>2+</sup> is pathologically involved in cancers, diabetes, and neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and demyelination. In the research field regarding the roles and mechanisms of Mg<sup>2+</sup> regulation, numerous controversies caused by its versatility and complexity still exist. As Mg<sup>2+</sup>, at least, plays critical roles in neuronal development, healthy normal functions, and diseases, appropriate Mg<sup>2+</sup> supplementation exhibits neurotrophic effects in a majority of cases. Hence, the control of Mg<sup>2+</sup> homeostasis can be a candidate for therapeutic targets in neuronal diseases. In this review, recent results regarding the roles of intracellular Mg<sup>2+</sup> and its regulatory system in determining the cell phenotype, fate, and diseases in the nervous system are summarized, and an overview of the comprehensive roles of Mg<sup>2+</sup> is provided.
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