The present treatment of solid tumors is plagued by drug resistance. Despite continued development of meticulously designed therapeutic scheme, cancer cells remain poorly being completely eliminated. Because therapeutic resistance is a problem with the drug used in cancer therapy, most of the studies about the drugs resistance have focused on the role of epithelial cancer cells themselves. However, it is becoming increasingly apparent that tumor microenvironment could provide a shelter for tumor cells which keep their survival after initial drug exposure. Cancer-associated fibroblasts (CAFs) are the crucial component of the tumor microenvironment; substantial evidence suggests that the CAFs mediate resistance of solid tumor cells to the anticancer drugs. In this review, we describe how the CAFs may be involved in the resistance of tumor cells to the therapeutic agents and present some of the emerging therapeutic targets for modulation this resistant phenotype.