The last two decades have witnessed a paradigm shift from cytotoxic drugs to targeted therapy in medical oncology 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 efficacy and minimized adverse effects compared with traditional treatments, the challenging drug-resistant issue has also emerged to limit their benefits to cancer patients. In this regard, we aim to improve targeted therapy by presenting a systematic framework regarding the drug resistance mechanisms and alternative approaches to re-sensitize cancer cells/tissues therapeutically.