Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for cancer therapy. It is well documented that cancer cells can adapt to the presence of chemotherapeutic agents through mutations or expression changes of key genes that control drug metabolism or response to damage. In addition, it is becoming increasingly apparent that the tumor microenvironment can have an important impact on the success of chemotherapy. Indeed, cell-cell and cell-matrix interactions can influence the cancer cells sensitivity to apoptosis and affect drug resistance. A model is proposed in which the tumor cells may actively reorganize their environment to maximize their survival in the presence of anticancer agents.