One of the most common and serious side effects of diuretic therapy is in increased urinary loss of K. Another, although less well publicized, side effect of diuretic therapy is excessive urinary loss of Mg. In examining the effects of diuretics on Mg and K metabolism, the following factors should be taken into account: site of action and duration of action of diuretics, duration of treatment and dosage used, concurrent drug therapy, underlying disease conditions and dietary intake of Mg. Diuretics acting in the proximal tubule tend to have only minor effects on Mg excretion. Loop-blocking diuretics, however, cause major urinary losses of Mg. The Mg-wasting effects of loop-blocking diuretics have been demonstrated in large numbers of experimental and clinical studies, and the findings are consistent with micropuncture studies in laboratory animals which indicate the loop of Henle as the major site of Mg reabsorption. The effects of thiazide diuretics on Mg excretion are less well established than those of loop-blocking diuretics. Experimental studies demonstrate that thiazides have little or no direct effect on Mg transport in the nephron. However, some clinical studies indicate that thiazide treatment may induce Mg loss. This may be secondary to alterations in the renin-angiotensin-aldosterone system and in the calcium and parathyroid hormone and may be contributed to by concurrent drug treatment and the underlying disease conditions. K-sparing diuretics are usually administered concomitantly with more potent diuretics to counteract diuretic-induced K depletion. These agents act in the late distal tubule and collecting duct. Evidence has accumulated in recent years indicating that these drugs may also exert some Mg-sparing properties. Experimental and clinical investigations from our own laboratories and from other investigators will be reviewed. In animal studies, a dose-response relationship has been established for the actions of amiloride in reducing fractional excretion of Mg and K during furosemide-induced diuresis. The effects of amiloride on Mg excretion are less than those on K excretion, and this is compatible with the different handling of K and Mg in the distal tubule and collecting duct. The effects of aldosterone antagonists on Mg excretion are less well established than those of amiloride. Some recent studies indicate that converting-enzyme inhibitors may also influence Mg and K metabolism. The Mg-sparing actions of drugs may have important therapeutic implications.