Abstract: Hepatocellular carcinoma (HCC) is one of the common malignant tumors in China. The most important treatment for middle-late stage HCC is chemotherapy. However, the development of multidrug resistance (MDR) in HCC can dramatically reduce the efficacy of chemotherapeutic treatment. At present, the mechanisms regulating the development of MDR in HCC are still unknown. These mechanisms involve ATP-dependent drug efflux pump, enzymatic deactivation, the activation of MAPK signal pathway, apoptosis gene and protein changing, the influence of the tumor microenvironment, and so on. With the development of the research, some new mechanisms are found, such as the endoplasmic reticulum stress and the effect of microRNA, which cannot be ignored. This review aims to summarize the mechanisms of MDR in HCC and discuss potential therapeutic targets for anticancer intervention.