Podophyllotoxin is an aryltetralin lignan lactone derived from different plants of Podophyllum. It consists of five rings with four chiral centers, one trans-lactone and one aryl tetrahydronaphthalene skeleton with multiple modification sites. Moreover, podophyllotoxin and its derivatives showed lots of bioactivities, including anticancer, anti-inflammatory, antiviral, and insecticidal properties. The demand for podophyllotoxin and its derivatives is rising as a result of their high efficacy. As a continuation of our previous review (Chem. Eur. J., 2017, 23, 4467-4526), herein we summarized total synthesis, biotransformation, structural modifications, bioactivities, and structure-activity relationships of podophyllotoxin and its derivatives from 2017 to 2022. Meanwhile, we compiled an update information on the origin of new podophyllotoxin analogues from plants from 2014 to 2022. We hope that this review will provide a reference for future high value–added applications of podophyllotoxin and its analogues in the pharmaceutical and agricultural fields