American Podophyllum has long been used by native Americans as a vermifuge and emetic and the subsequently obtained resin was employed as a purgative. Its use however declined until 1942 when the resin was recommended for the treatment of veneral warts. Indian Podophyllum has been used in Ayurveda and Unani systems of medicine as purgative, cholagogue, emetic and against warts. Ripe fruits are edible and used against fever. Tibetan medicine uses it for gynecological disorders. Podophyllotoxin and other Podophyllum lignans were found unsuitable for clinical use as anti-cancer agents due to toxic side effects, but the semi-synthetic derivatives etoposide and teniposide made from natural podophyllotoxin have proved excellent anti-tumour agents. They were developed as modified forms (acetals) of the natural 4′-demethyl podophyllotoxin glucoside. Etoposide is a very effective anti-cancer agent and is used in the treatment of small-cell lung cancer, testicular cancer as well as lymphomas and leukemias usually in combination therapy with other anti-cancer drugs. Teniposide has similar anti-cancer properties, and though not as widely used as etoposide has value in paediatric neuroblastoma.

These drugs inhibit the enzyme topoisomerase II, thus preventing DNA synthesis and replication. Topoisomerases are responsible for cleavage and resealing of DNA strands during the replication process. The overall effect of these drugs is the arrest of the cells in late S or early G2 phase of the cell cycle. The anti-mitotic and purgative properties of these compounds depend on a lactone ring in trans configuration.