The established efficacy of doxorubicin in the medical treatment of cancer is hampered by dose limiting side effects and lack of activity on major clinical tumors. The new derivative epirubicin (4'-epidoxorubicin) is already available clinically as a better tolerated drug, with confirmed efficacy on doxorubicin responsive diseases. Because of the different orientation of the 4'-hydroxyl, the compound is partially detoxified in the human body by beta-glucuronidation. The other clinically studied analogue, idarubicin (4-demethoxydaunorubicin), has shown clinical activity in leukemias and in breast tumors also when given p.o. The properties of idarubicin may be related to electronic factors and to the extensive bioconversion to 13(S)-idarubicinol. New lines of investigation are introduced. The first is represented by the irreversible DNA binding derivatives and is exemplified by the highly potent cyanomorpholino analogues. The second is based on the finding that certain structural modifications, such as in the 6-deoxy derivatives, are accompanied by resistance to enzymic reductive deglycosidation, a reaction that converts the anthracyclines to inactive compounds in hypoxic conditions. The third line of investigation deals with the very lipophilic doxorubicin analogues, among which 4'-deoxy-4'-iododoxorubicin has been selected for further preclinical development because of the extended spectrum of activity also after p.o. administration and of the cytotoxicity exhibited on doxorubicin-resistant murine leukemia cells.