Glucocorticoids such as dexamethasone, frequently used for the treatment of multiple myeloma (MM), produce a rapid reduction in tumor mass. However, despite frequent initial complete remission, prolonged dexamethasone treatment results in the appearance of chemoresistant tumor cells and most patients with MM ultimately present relapse of the underlying disease. Accumulating data suggest that bone marrow components such as cytokines, extracellular matrix (ECM) and adjacent stroma cells could cooperate to provide a sanctuary to malignant plasma cells that allow their survival after initial drug exposure. This review focuses on the two major components of the bone marrow ECM that have been identified as mediators for innate or acquired drug resistance in MM, hyaluronan and fibronectin. These two ECM molecules are thought to play a crucial role in the pathogenesis of MM, combining their protective activities to promote optimal conditions for the long life of plasma cells and contribute to de novo drug resistance. They represent promising targets for the development of innovative treatments in order to prevent interactions between tumor cells and their microenvironment and to sensitize cancer cells to chemotherapy before the emergence of acquired mechanisms of chemoresistance.