The role of extrarenal potassium homeostasis is well recognized as a major mechanism for the acute defense against the development of hyperkalemia. The purpose of this report is to examine whether or not the various mechanisms of extrarenal potassium regulation are intact in patients with end-stage renal disease (ESRD). The available data suggest that with the development of ESRD and the uremic syndrome there is impaired extrarenal potassium metabolism that is related to a defect in the Na,K-adenosine triphosphatase (ATPase). The responsiveness of uremic patients to the various effector systems that regulate extrarenal potassium handling is discussed. Insulin is well positioned to play an important role in the regulation of plasma potassium concentration in patients with impaired renal function. The role of basal insulin may be even more important than previously appreciated, since somatostatin infusion causes a much greater increase in the fasting plasma potassium in rats with renal failure than in controls. Furthermore, stimulation of endogenous insulin by oral glucose results in a greater intracellular translocation of potassium in uremic rats than in controls. Under at least two common physiologic circumstances, feeding and vigorous exercise, endogenous catecholamines might also act to defend against acute increments in extracellular potassium concentration. However, it is important to appreciate that the response to beta 2-adrenoreceptor-mediated internal potassium disposal is heterogeneous as judged by the variable responses to epinephrine infusion. Based on the evidence presented in this report, a regimen for the treatment of life-threatening hyperkalemia is outlined. Interpretation of the available data demonstrate that bicarbonate should not be relied on as the sole initial treatment for severe hyperkalemia, since the magnitude of the effect of bicarbonate on potassium is variable and may be delayed. The initial treatment for life-threatening hyperkalemia should always include insulin plus glucose, as the hypokalemic response to insulin is both prompt and predictable. Combined treatment with beta 2-agonists and insulin is also effective and may help prevent insulin-induced hypoglycemia.