Anthracyclines are useful chemotherapeutic agents whose utility is limited by the development of irreversible cardiotoxicity. When tested, the pediatric population demonstrates an increased sensitivity to the cardiotoxicity of this class of agents, although the reasons for this increased sensitivity are unclear. The sarcoplasmic reticulum (SR) is a target for anthracycline cardiotoxicity in adults, but the effects of anthracycline on the SR in developing myocardium have not been examined. It may be possible to gain insight into the mechanisms of cardiotoxicity through a comparative approach. We compared the acute effects of doxorubicin, daunorubicin, and caffeine on contractile function in adult and neonatal rabbit myocardium. Frequency-dependent contractility, 90% relaxation times, and postrest potentiated contractions (a uniquely SR-dependent phenomenon) in adult myocardium were inhibited in a concentration- dependent manner. Neonatal myocardium, however, was resistant to the effects of these agents. The degree of contractile dysfunction was consistent with the difference in SR maturation between adult and developing myocardium. Anthracyclines exhibited effects similar to those of caffeine, an agent known to render the SR nonfunctional by the depletion of the releasable SR calcium pool. These results suggest that anthracyclines induce acute cardiac lesions through effects on the SR in adults, whereas cardiotoxic effects in the developing myocardium may proceed by a different mechanism.