The last two decades have witnessed a paradigm shift from cytotoxic drugs to targeted therapy in medical oncol?ogy and pharmaceutical innovation. Inspired by breakthroughs in molecular and cellular biology, a number of novel synthesized chemical compounds and recombinant antibodies have been developed to selectively target oncogenic signaling pathways in a broad array of tumor types. Although targeted therapeutic agents show impressive clinical eicacy and minimized adverse efects compared with traditional treatments, the challenging drug?resistant issue has also emerged to limit their beneits to cancer patients. In this regard, we aim to improve targeted therapy by present?ing a systematic framework regarding the drug resistance mechanisms and alternative approaches to re?sensitize cancer cells/tissues therapeutically. The last two decades have witnessed a paradigm shift from cytotoxic drugs to targeted therapy in medical oncol? Ogy and pharmaceutical innovation. Inspired by breakthroughs in molecular and cellular biology, a number of novel synthesized chemical compounds and recombinant antibodies have been developed to selectively target oncogenic signaling pathways in a broad array of tumor types. While targeted therapeutic agents show impressive clinical eicacy and minimized adverse efects compared with traditional treatments, the challenging drug? to improve targeted therapy by present? ing a systematic framework regarding the drug resistance mechanisms and alternative approaches to re? sensitize cancer cells / tissue therapeutically.