There is considerable evidence that the central nervous system (CNS) is significantly involved in potassium homeostasis: (a) Potassium-specific receptors located in the liver or hepatic portal circulation initiate a reflex increase in potassium excretion via vagal afferents. This reflex is lost or diminished with hypophysectomy. (b) Oscillators, presumably located in the hypothalamus, determine a circadian rhythm in the renal excretion of potassium. The efferent control factors are unknown. (c) Exogenous hypophysial peptides (vasopressin, oxytocin, and alpha-, beta-, and gamma-MSH) stimulate increased potassium (and sodium) excretion. (d) Hypophysial gamma-MSH or a related hypophysial peptide stimulates an increase in the excretion of potassium (and sodium) following uninephrectomy in the rat. This adaptive response involves cerebral, naloxone-inhibitable opioid receptors. (e) Intra-third-ventricular infusion of hypertonic NaCl initiates an increased potassium (and sodium) excretion through undetermined humoral mechanisms and is blocked by prior hypophysectomy. (f) In rats depleted of potassium by low potassium intake or by production of DOCA hypertension, an inhibition of skeletal muscle Na+, K(+)-ATPase ion pump activity is directed by hypothalamic centers and involves inhibition by alpha-adrenergic activity of slow twitch fibers and inhibition by undetermined humoral factors of fast twitch fibers. (g) Potassium receptors, either demonstrated or inferred, initiate reflex increases in respiration, heart rate, blood pressure, and peripheral tissue potassium uptake as well as a reflex inhibition of skeletal muscle ion pumps. (h) Evidence for CNS regulation of potassium intake is equivocal. Major gaps exist in this emerging picture of neuroendocrine involvement in potassium homeostasis.