Normal potassium homeostasis is regulated by both renal and extrarenal mechanisms. Although chronic potassium balance is primarily regulated by the kidneys, acute potassium tolerance is largely determined by extrarenal tissues. During the first 4-6 h following an acute potassium load, only about 50% of the potassium is excreted by the kidneys. Of the remaining 50% that is retained, over 80% is translocated into cells, and this provides the primary defense against hyperkalemia. Potassium uptake by both liver and muscle and intestinal secretion of potassium are the most important mechanisms of extrarenal potassium disposal. Several hormones, including insulin and epinephrine, have been shown to play an important role in the maintenance of normal extrarenal potassium metabolism. These hormones function by enhancing potassium uptake by liver and muscle. There is also evidence that aldosterone is necessary in the maintenance of normal extrarenal potassium tolerance. Although the major extrarenal site of action of aldosterone has not yet been clearly defined, gastrointestinal potassium secretion and muscle transport of potassium are both affected by the hormone. Evidence exists that glucocorticoids may also have an effect on extrarenal potassium homeostasis. In addition to this hormonal regulation, cellular shifts of potassium are influenced by changes in acid-base balance. Extrarenal potassium tolerance is impaired in chronic renal insufficiency. These uremia-related changes are discussed in the context of our present understanding of normal extrarenal potassium metabolism.