Mammalian cells tightly regulate cellular Mg(2+) content through a variety of transport and buffering mechanisms under the control of various hormones and cellular second messengers. The effect of these hormones and agents results in dynamic changes in the total content of Mg(2+) being transported across the cell membrane and redistributed within cellular compartments. The importance of maintaining proper cellular Mg(2+) content optimal for the activity of various cellular enzymes and metabolic cycles is underscored by the evidence that several diseases are characterized by a loss of Mg(2+) within specific tissues as a result of defective transport, hormonal stimulation, or metabolic impairment. This chapter will review the key mechanisms regulating cellular Mg(2+) homeostasis and their impairments under the most common diseases associated with Mg(2+) loss or deficiency.