Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.

It was patented in 1966 and approved for medical use in 1974.

One of the primary uses of metolazone is for treating edema (fluid retention) associated with congestive heart failure (CHF). In mild heart failure, metolazone or another diuretic may be used alone, or combined with other diuretics for moderate or severe heart failure. In addition to preventing fluid buildup, the use of metolazone may allow the patient to relax the amount of sodium restriction that is required. Although most thiazide diuretics lose their effectiveness in kidney failure, metolazone remains active even when the glomerular filtration rate (GFR) is below 30–40 mL/min (moderate chronic kidney disease).^{[citation needed]} This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention.

Metolazone may also be used in kidney disease, such as chronic kidney disease or the nephrotic syndrome. Chronic kidney disease causes excess fluid retention that is often treated with diet adjustments and diuretics. Metolazone may be combined with other diuretics (typically loop diuretics) to treat diuretic resistance in congestive heart failure, chronic kidney disease, and nephrotic syndrome. Metolazone and a loop diuretic will synergistically enhance diuresis over the use of either agent alone. Using this combination, diuretic effects will occur at two different segments of the nephron; namely, the loop diuretic will act at the loop of Henle, and metolazone will act at the distal convoluted tubule. Metolazone is frequently prescribed in addition to the loop diuretic. Metolazone may be used for edema caused by liver cirrhosis as well.

The other major use of metolazone is in treating hypertension (high blood pressure). Thiazide diuretics, though usually not metolazone, are very often used alone as first-line treatment for mild hypertension. They are also used in combination with other drugs for difficult-to-treat or more severe hypertension. "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) recommends thiazide diuretics as the initial medication for treatment of hypertension. Hydrochlorothiazide is by far the most commonly used, as it is both better-studied and cheaper (about four times) than metolazone, although as mentioned above metolazone is used in patients with moderate chronic kidney disease.

Since thiazide diuretics affect the transport of electrolytes and water in the kidney, they can be responsible for abnormalities of water balance and electrolyte levels. Removal of too much fluid can cause volume depletion and hypotension. Various electrolyte abnormalities may result, including hyponatremia (low sodium), hypokalemia (low potassium), hypochloremia (low chloride), hypomagnesemia (low magnesium), hypercalcemia (high calcium), and hyperuricemia (high uric acid). These may result in dizziness, headache, or heart arrhythmias (palpitations). Serious, though rare, side effects include aplastic anemia, pancreatitis, agranulocytosis, and angioedema. Metolazone, like other thiazide diuretics, may unmask latent diabetes mellitus or exacerbate gout, especially by interacting with medicines used to treat gout. In addition, thiazide diuretics, including metolazone, are sulfonamides; those with hypersensitivity to sulfonamides ("sulfa allergy") may also be allergic to metolazone.

The primary target of all thiazide diuretics, including metolazone, is the distal convoluted tubule, part of the nephron in the kidney, where they inhibit the sodium-chloride symporter.

In the kidney, blood is filtered into the lumen, or open space, of the nephron tubule. Whatever remains in the tubule will travel to the bladder as urine and eventually be excreted. The cells lining the tubule modify the fluid inside, absorbing some material and excreting others. One side of the cell (the apical side) faces the lumen; the opposite side (the basolateral side) faces the interstitial space near blood vessels. The other sides are tightly joined to neighboring cells.