While studying certain coelenterates for antitumor activity, crude aqueous-ethanolic extracts were found to be very highly toxic to mice, and they exhibited potent cardiotoxicity to rats. When tested at sublethal concentrations, extracts of the sea anemones Anthopleura xanthogrammica (Brandt) and A. elegantissima (Brandt) showed a powerful positive inotropic effect with no chronotopic effect. Further pharmacological studies indicated that the adrenergic system was not involved in the mechanism of action, Na+,K+-ATPase was not inhibited, and vascular tissue was not affected by the extracts. Two cardiotonic polypeptides were then isolated from A. xanthogrammica and named anthopleurin-A (AP-A) and anthopleurin-B (AP-B). A third cardiotonic polypeptide, anthopleurin-C (AP-C), was isolated from A elegantissima. AP-A and AP-C have been sequenced and AP-B partially sequenced. Studies of carbon-13 nuclear magnetic resonance, circular dichroism, laser-Raman and fluorescence spectroscopy have given some clues as to tertiary structure. Chemical amino acid blocking studies also have provided some information as to which functional groups are required for activity. AP-A has been thoroughly studied pharmacologically, but the exact mechanism of action is still not known.