Diuretic drugs have marked effects on lithium clearance. The magnitude and mechanism of the effect depend not only on the site of action of the diuretic but also on the sodium intake of the subject as well. In sodium restricted rats all diuretics except the thiazides increase FeLi and abolish distal lithium uptake. The increase in FeLi produced by proximal and loop diuretics are associated with changes in proximal delivery. Amiloride, on the other hand, increases FeLi solely through inhibition of distal lithium uptake. Therefore, this agent is useful to detect lithium reabsorption beyond the proximal tubule. Additionally the values for FeLi obtained after amiloride administration may provide the best quantitative estimate for proximal delivery in conditions where distal lithium uptake is a consideration. Antidiuretic agents, especially those which potentiate ADH activity, may also have marked effects on lithium clearance. NSAID's and dDAVP are able to significantly reduce FeLi even in sodium loaded animals. As this occurs without a change in proximal delivery, these agents increase lithium reabsorption in distal nephron segments preferentially. Thus, estimates of proximal delivery determined by lithium clearance are not valid in the presence of these agents. Experimental conditions which produce high levels of endogenous ADH or potentiate the action of endogenous ADH may also adversely effect FeLi as a quantitative marker for proximal delivery. Whether there are other drugs which disrupt the ability of lithium clearance to function as a marker for proximal delivery requires further study.