<p>Cancer evolution can engender tumours with the ability to resist multiple treatments with distinct chemical structures and mechanisms of action, and this multidrug resistance (MDR) phenotype has long been a substantial challenge in cancer therapy. Despite the established benefits of systemic treatments including chemotherapies, molecularly targeted therapies and immunotherapies across various cancers, MDR inevitably occurs at some point during the course of the disease and its treatment in most patients. Since the discovery of MDR in the 1960s, our understanding of the underlying mechanisms has deepened. However, few strategies are currently available to combat MDR in the clinical setting, and approaches to systematically translate knowledge of new MDR mechanisms and treatments from the laboratory into the clinic are lacking. In this Review, we focus on preclinical and clinical advances in understanding MDR, with an emphasis on resistance to chemotherapy and targeted therapy. We also summarize progress made in translating these findings from bench to bedside through the development of potential strategies to overcome MDR and thus improve patient outcomes.</p>