The efficacy and toxicity of the siderophore desferrithiocin (DFT), which has shown potential application in iron chelation therapy, were assessed in vivo and in vitro. DFT was evaluated in vivo in two ways: firstly, by measuring the effect of a single dose of DFT (10-100 mg/kg) on 59Fe excretion in iron-loaded rats labelled with 59Fe; and secondly, by examining the effect of the daily oral administration for 2 weeks of DFT (10-25 mg/kg/d) on the growing rat. DFT and its ferric complex, ferrithiocin (FT), were assessed in vitro from their effects on transferrin and iron uptake and mobilization from rat hepatocytes in culture using transferrin doubly labelled with 125I and 59Fe. Both oral and subcutaneous DFT were highly effective in promoting iron excretion in vivo, but showed evidence of toxicity after oral administration for 2 weeks at 25 mg/kg/d. In addition, DFT was much more effective than desferrioxamine or pyridoxal isonicotinyl hydrazone in reducing hepatocyte iron in vitro. However, FT was cytotoxic, causing membrane disruption and release of intracellular aspartate aminotransferase. It was concluded that DFT should not be considered for chronic iron chelation therapy without extensive further evaluation.