Quantitative structure-activity relationships (QSAR) are developed for both the antitumor activity (B-16 melanoma) and cardiotoxicity of a set of anthracycline derivatives, for the purposes of finding exploitable differences between the two which would lead to improvements in the therapeutic indices of these compounds. It was found that most structural features which lead to improvement in antitumor activity, such as increases in drug hydrophilicity, also lead to increases in cardiotoxicity. However, demethoxylation and demethoxylation at the 4-position of these molecules appears to have much greater effect on cardiotoxicity than on antitumor activity. If these effects are brought about by alterations in the oxidation-reduction potential of the quinone structure, as is suggested, then it may be possible to make analogs with a better therapeutic index by the introduction of small hydrophilic electron-releasing groups in the A-ring of these adriamycin derivatives that are conjugated with the carbonyl functions.