Clinically, chemotherapy is the mainstay in the treatment of multiple cancers. However, highly adaptable and activated survival signaling pathways of cancer cells readily emerge after long exposure to chemotherapeutics drugs, resulting in multi-drug resistance (MDR) and treatment failure. Recently, growing evidences indicate that the molecular action mechanisms of cancer MDR are closely associated with abnormalities in saccharides. In this review, saccharides affecting cancer MDR development are elaborated and analyzed in terms of aberrant aerobic glycolysis and its related enzymes, abnormal glycan structures and their associated enzymes, and glycoproteins. The reversal strategies including depletion of ATP, circumventing the original MDR pathway, activation by or inhibition of sugar-related enzymes, combination therapy with traditional cytotoxic agents, and direct modification on the sugar moiety, are ultimately proposed. It follows that abnormal saccharides have a significant effect on cancer MDR development, providing a new perspective for overcoming MDR and improving the outcome of chemotherapy. Copyright © 2021 Elsevier Masson SAS. All rights reserved.