Parthenolide: from plant shoots to cancer roots

•This article highlights phases in parthenolide (PTL) lead anticancer drug development.•PTL structure–activity relationship studies reveal properties required for potency and bioavailability.•PTL is selective to biological and/or epigenetic targets, tumors and CSCs.•PTL targets multiple pathways of tumor survival, seeding and self-renewal.•PTL pharmacology and use in animal models have clinical implications. Parthenolide (PTL), a sesquiterpene lactone (SL) originally purified from the shoots of feverfew (Tanacetum parthenium), has shown potent anticancer and anti-inflammatory activities. It is currently being tested in cancer clinical trials. Structure–activity relationship (SAR) studies of parthenolide revealed key chemical properties required for biological activities and epigenetic mechanisms, and led to the derivatization of an orally bioavailable analog, dimethylamino-parthenolide (DMAPT). Parthenolide is the first small molecule found to be selective against cancer stem cells (CSC), which it achieves by targeting specific signaling pathways and killing cancer from its roots. In this review, we highlight the exciting journey of parthenolide, from plant shoots to cancer roots.