The bisdioxopiperazine dexrazoxane (DEX; ICRF-187) has proven to be clinically effective in reducing the cardiotoxicity of doxorubicin and the toxicity of other anthracyclines. Doxorubicin and the other anthracyclines are thought to exert their toxicity through iron-based oxygen free radical-induced oxidative stress on the relatively unprotected cardiac muscle. On hydrolysis, DEX forms a compound (ADR-925) similar in structure to EDTA, which, like EDTA, is a strong chelator of iron and other metal ions. Dexrazoxane presumably exerts its cardioprotective effects by either binding free or loosely bound iron, or iron complexed to doxorubicin, thus preventing or reducing site-specific oxygen radical production that damages cellular components. The hydrolysis-activation of DEX to ADR-925 can occur through either enzymatic or nonenzymatic routes. Iron(III)-anthracycline complexes are directly able to promote ring-opening hydrolysis of DEX. Both ferrous and ferric ions (as well as several other divalent metal ions) can promote the hydrolysis of the one-ring open intermediates of DEX to ADR-925, which suggests that these intermediates may be pharmacologically active. Paradoxically, the ferric complex of ADR-925 has been shown to be capable of being reductively activated to mediate hydroxyl radical formation. This observation suggests that DEX may be acting through its ability to prevent site-specific oxygen radical damage by iron-anthracycline complexes.