The relations between renin release and renal hemodynamics, renal sodium load, and sodium and water balance were studied during hyponatremia, hypernatremia, mercurial natriuresis, norepinephrine infusion, and reduction in renal perfusion pressure. Significant reciprocal relations were found between renin secretory activity and the renal arterial plasma sodium concentration, the filtered sodium load, and urinary sodium excretion; however, no significant, or even consistent, relations were found between renin release and any hemodynamic parameter or sodium or water balance. During bilateral stimulation of renin release, unilateral restoration of the filtered sodium load inhibited ipsilateral renin release, without demonstrable changes in hemodynamics, while renin release from the contralateral kidney continued unabated. However, this inhibition was not seen unless the filtered sodium load and urinary sodium excretion rose to control levels even though renal venous plasma sodium concentrations exceeded 170 mEq/liter. Thus, renin release can be dissociated from hemodynamics and sodium and water balance, but not from some function of the filtered sodium load. We propose that renin secretory activity is controlled by an intrarenal, but extravascular, sodium-sensitive mechanism and that the stimulus is a function of the sodium flux across the macula densa into the interstitium surrounding the contiguous juxtaglomerular cells.