Podophyllotoxins, including epipodophyllotoxin derivatives, can act on a diverse array
of drug targets in cancer cells and thus possess potent activity against various forms of cancer cell
lines, including drug-resistant forms. Moreover, several podophyllotoxin derivatives represented
by etoposide and teniposide, have already been approved for cancer therapy, demonstrating podophyllotoxin
moiety as a useful pharmacophore for the discovery of novel anticancer agents. This review
reports the recent advances in the exploitation of podophyllotoxin derivatives to fight against
multidrug-resistant cancer cells. The mechanism of action and structure-activity relationship (SAR)
studies are also highlighted.