Abstract: The advantages of combining traditional Chinese medicine (TCM) and western medicine for treating tumors include enhancement of treatment efficiency and reduction of toxicity. The resistance of cancer cells to anticancer drugs remains a critical issue in cancer treatment. TCMs have the ability to increase the sensitivity of cancer cells to anticancer drugs and overcome drug resistance through their multi-component, multi-target, and multi-stage mechanisms. However, the components are complex and the specific mechanisms are unclear. To overcome drug resistance, modern medicine advocates the replacement of anticancer agents with those of a new generation. However, these drugs often have single targets, result in greater side effects, and easily induce multidrug resistance, which limits the efficacy of anticancer treatment. Based on the compatibility theory of TCM, "Jun-Chen-Zuo-Shi," we studied several Chinese medicines with a chemotherapeutic sensitization effect and the ability to reverse drug resistance. Additionally, we extracted their effective ingredients and determined their possible molecular mechanisms. Furthermore, multiple active molecules with clear ingredients, structure, efficacy, and mechanism were optimized to form a compound with "molecular compatibility" and the ability to generate a synergistic anticancer effect, decrease the dose of each individual compound, reduce individual drug-related toxicity, and suppress multidrug resistance through different mechanisms. Understanding the scientific connotation of "molecular compatibility" by combining TCM and western medicine would provide a new strategy for overcoming cancer drug resistance.