Piplartine, also known as piperlongumine, is an amide alkaloid that occurs naturally in several Piper species. It has attracted considerable attention in recent times due to its potential antineoplastic properties, and has now been considered an important prototype for new anticancer drugs development. Piplartine kills cancer cells through oxidative stress and several cell signaling pathways have been associated with piplartine-induced cell death, including the p53, NF-κB, MAPK, STAT3, and PI3K/Akt/mTOR pathways. In this chapter, we summarize the main features of piplartine in the induction of oxidative stress and its usage perspective in cancer therapy. © 2021 Elsevier Inc.