The composition of the extracellular matrix in tumors is vastly different from that found in the normal tissue counterparts. As the extracellular matrix can signal to cells via integrin binding and activation, which is known to modulate cell proliferation, survival and migration, it may influence the response of both tumor and endothelial cells to anticancer therapies. Certain tumor-associated extracellular matrix proteins have been shown to confer resistance to chemotherapeutic drugs, radiation and anti-angiogenic factors. The current literature regarding this phenomenon and the potential therapeutic modalities to overcome extracellular matrix-induced resistance will be discussed.