Multidrug resistance remains the major hurdle to successful cancer treatment. Classical mechanisms of multidrug resistance include drug efflux pumps, glutathione-S-transferase upregulation and topoisomerase II-associated multidrug resistance. However, despite extensive research, the clinical relevance of these mechanisms remains unclear and no significant clinical benefit has materialized. Recently, a novel mechanism of multidrug resistance has been identified--extracellular matrix-mediated multidrug resistance: integrin-mediated adherence of cells to extracellular matrix proteins results in significant resistance to many anticancer agents that induce cell death via unrelated mechanisms. Verification of the mechanisms of action of this novel phenomenon will hopefully identify new therapeutic targets to aid in the fight against cancer.