Dietary sodium restriction has several clinical benefits, particularly that of enhancing the antihypertensive action of diuretics and other blood pressure-lowering drugs. In individuals who form hypercalciuric stones, sodium restriction along with thiazide diuretics helps to reduce urinary calcium. However, there are adverse consequences of sodium restriction, particularly in elderly patients with impaired sodium conservation mechanisms. Ischemic and nephrotoxic injuries are induced more readily in sodium-depleted animals and patients because of impaired renal hemodynamics and activation of the renin-angiotensin system. Acute renal failure can be precipitated by sodium restriction and concomitant angiotensin-converting enzyme inhibitors, nonsteroidal antiinflammatory drugs, and immunosuppressive drugs. Dietary sodium restriction in animals enhances the chronic nephrotoxicity of cyclosporine and tacrolimus, whereas similar doses of these drugs do not produce structural damage in salt-replete animals. Maneuvers that block angiotensin II protect against renal scarring and drug-induced arteriolopathy in this model. Sodium restriction can enhance the renal tubular reabsorption of drugs such as lithium, leading to toxic blood concentrations. Calcium antagonists may have better efficacy when prescribed to salt-replete hypertensive persons. Finally, there is evidence that activation of the renin-angiotensin system by sodium depletion will enhance the growth of cysts in animal models of cystic renal disease. In individual patients, the effects of sodium restriction by diet should balance anticipated benefits against any possible adverse consequences.