The nephrotic syndrome is associated with an expanded interstitial volume and edema due to sodium and water retention. The mechanisms underlying these abnormalities have been only partially clarified. Renal hypoperfusion has been considered the key event that promotes avid sodium and water reabsorption by the kidney. Hypoperfusion results from hypovolemia, a consequence of urinary protein losses and decreased oncotic pressure. However, in some patients plasma volume is normal or even increased, suggesting that in such cases the cause of sodium and water retention might be independent of systemic events and possibly originates in the kidney. Experimental evidence is now available to support this, but the intrarenal mediator(s) that promote the abnormal salt retention are still not fully clear. Atrial natriuretic peptide (ANP), which increases sodium and water excretion, has been suspected to participate in fluid retention. This is consistent with experimental and human data of a markedly blunted natriuretic and diuretic response to systemic infusion of ANP in the nephrotic syndrome. Recent studies of the mechanisms of the blunted natriuretic and diuretic response to ANP documented an increased activity of renal sympathetic nerves, but the results are controversial. The altered response to ANP also may be related to a defect in the number and affinity of receptor-binding sites for the peptide. Evidence also is available of a possible defect at the level of intracellular cyclic guanosine monophosphate, the second messenger of ANP. The gene encoding for a cyclophilin-like protein, which is increased in sodium-retaining conditions, is upregulated in the kidneys of nephrotic rats, and the infusion of ANP further increases cyclophilin-like protein mRNA. Thus, multiple factors probably act in concert to induce edema formation in the nephrotic syndrome. In this review we specifically address the tubular insensitivity to the natriuretic and diuretic action of ANP, which could be an important initiating event and could possibly contribute to sustaining the edema.