**Abstract**

The incidence of multidrug resistance (MDR) during treatment is rising, persisting and spreading globally due to the emergence of resistance to multiple antibiotics. This is a serious challenge that is causing clinical failures in the treatment of infections and diseases, persistent illnesses, higher costs for health maintenance, higher risk of mortality and threat to public health. It is widely acknowledged that polyphenols present in citrus fruits exhibit beneficial effects in the inhibition of MDR, and as such, they could serve as appealing potential therapeutics in this regard. Some of the mechanisms citrus polyphenols employed in preventing the occurrence of MDR in cancer and bacterial cells have been identified. They include the initiation of apoptosis through modulation of the PI3K/Akt pathway, inhibition of P-glycoprotein function, enhancement of the intracellular accumulation of drugs, arrest of the cell cycle at G0/G1 phase, downregulation of the expression of pro-inflammatory cytokines and others. Taking into account the significance of MDR, this review highlights the mechanisms of MDR and the potential inherent in citrus polyphenols in fruits in reversing it.

**Keywords:** multidrug resistance, citrus, polyphenol, signaling pathway, flavonoids
