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Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual\u2010target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual\u2010target drugs, especially focusing on pharmacological small\u2010molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. 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