The cancer cell resistance to current anticancer therapeutics as well as their causing side effects are still obstacles to successful cancer therapy.Hence,development of new anticancer agents or therapeutics are of vital significance, especially rational combination therapies containing low-cost natural products with multiple targets, which has attracted great interests. Triptolide, the main biocomponent of Tripterygium wilfordii Hook F, is restricted in clinical applications mainly due to its severe systemic toxicities, though it has shown strong antitumor activities in preclinical studies. Mounting evidences suggest that using triptolide at low doses as an adjuvant therapeutic agent circumvents resistance to current anticancer therapies, enhances the anticancer effectiveness, and relieves toxicities of both triptolide and anticancer therapies. The molecular mechanisms of triptolide-induced anti-resistance and sensitization effects include change in enzymes and ABC transporters, induction of cell death pathways,increase of tumor suppressors and decrease of oncogenic factors, and interactions with the RNA polymerase II complex; besides, targeting to cancer stem cells and tumor-microenvironment-meiated resistance and alternations in epigenetics are also involved. This review summarizes the broad targeting of triptolide to resistance and sensitization for cancer therapy; its semi-synthetic derivatives and novel delivery systems which are developed to enhance the solubility and reduce the toxicity will also be discussed.