Most of the anticancer chemotherapy are hampered via the development of multidrug resistance (MDR), which is resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, change in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR. Here we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. To do so, Pubmed and Scopus have been searched using Wnt, β-catenin, cancer, MDR and multidrug resistance as keywords. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical and non-canonical pathways. Wnt/β-catenin signaling has also linked to other pathways such as NF-κB and PI3K-Akt involving cancer progression. Accordingly, Wnt/β-catenin signaling can be a potential target for cancer therapy. Copyright© Bentham Science Publishers; For any queries, please email at [email protected].