**1. Introduction**

Multidrug resistance (MDR) is one of the major factors contributing to a failure of doxorubicin for cancer treatment. Typically, the loss of cell sensitivity to chemotherapy is not limit to only doxorubicin and anthracycline derivatives. The MDR phenomenon evidently extends across various structurally-unrelated anticancer drugs, regardless of their molecular targets [1–3]. Hence, MDR development in cancer cells can simultaneously reduce the effectiveness of several cytotoxic drugs, leading to chemotherapeutic failure. Consequently, patients need higher doses of the anticancer agents to achieve therapeutic success. Either intrinsic or acquired resistance to doxorubicin-based chemotherapy has been attributed to various mechanisms including high expression of the drug efflux transporters, alteration of cell cycle checkpoints and apoptotic signals, increased drug detoxification and DNA repair processes [4–6]. Regarding this, MDR reversal can be one of the strategic approaches to enhance the efficacy, without increased adverse events, of doxorubicin.

This chapter focused on the most studied drug efflux transporter P-glycoprotein (P-gp) and its role in doxorubicin resistance in chemotherapy. In addition, some strategic approaches to conquer P-gp-based MDR in cancer treatment were also described.
