Abstract: The aryltetralin-type lignan podophyllotoxin, the main agent present in the resin extracted from the rhizomes of different podophyllum species, possesses important antineoplastic and antiviral properties and has been widely used in diverse cultures since ancient times for medicinal purposes as a cathartic and antihelminthic agent. Today, podophyllotoxin serves as the starting material for the preparation of the well-known cytostatic agents: etoposide and teniposide which are used in combination therapies with other drugs for the treatment of a variety of malignancies. The present review focuses on the lead compound, that is, podophyllotoxin and summarizes its structural characteristics, natural sources, biological activities, novel derivatives, medicinal applications and future perspectives.