The class of nephrotoxins which are directly tubulotoxic in animal studies (cis-platinum, gentamicin, and cephaloridine) produce minimal histological changes in the human kidney. Such alterations do not correlate with the degree of organ dysfunction and fall into the broad category of what has been called 'acute tubular necrosis'. Some nephrotoxins (cyclosporine and amphotericin), acutely and chronically diminish renal perfusion, causing injury to renal parenchymal zones known to have limited oxygen a availability (medullary ray and inner stripe). In cyclosporine toxicity, the human and animal models appear equivalent. This is less clear with amphotericin where there appears to be a tubulotoxic component. Other nephrotoxic substances (contrast, nonsteroidal anti-inflammatory drugs) acutely alter renal perfusion, particularly affecting the medulla. In animal models of renal failure induced by these substances, there is an excellent correlation between medullary thick ascending limb injury and renal failure. Documentation of this phenomenon in human biopsies/autopsies is lacking, probably because of the lack of biopsy material and problems in defining medullary injury. Finally, in toxicological screening programs for nephrotoxic substances, there are groups of reactions which cannot be predicted and are thought to be mediated by immune mechanisms, i.e., immune complex glomerular disease, nil disease and interstitial nephritis.