Atrial natriuretic factor, the first well defined natriuretic hormone is synthesized in the human heart as 151 aminoacid (AA) preprohormone and stored as 126 AA prohormone in atrial granules. Upon appropriate stimulation, the prohormone is cleaved into a 98 AA N-terminal fragment and a 28 AA C-terminal fragment, the biological active ANF(99-126), both circulating in plasma. Circulating ANF(99-126) is cleared by various organs, such as lung, liver and intestine, kidney and upper and lower limbs. Reported arterial-venous extraction ratios vary greatly, but are not much different between organs, the average extraction ratio being about 35%. Due to marked differences of organ blood flow, the contribution of various organs to total body ANF clearance differs considerably. Major mechanisms for ANF clearance are uptake by clearance receptors and degradation by an endoprotease (EC 3.4.24.11.). Clearance receptors, distinct from the receptors mediating the biological actions of ANF, have been demonstrated in various organs. Characterization of the ANF degrading enzyme activity has been performed in kidney tissue. Whether and how pathophysiological states affect ANF clearance is still poorly understood. Inhibition of clearance by ANF analogues binding to clearance receptors and by inhibitors of degrading peptidase can increase the biological action of circulating ANF. This may prove to be a therapeutic approach in diseases with smooth muscle contraction or volume overload.