Heat shock response is one of several survival pathways that protects cells against harsh conditions. This response mechanism, which is evolutionarily protected in all organisms, enhances the expression of heat shock proteins (HSP) that show protective properties for cells under stress conditions. High expression of many HSP is observed in cancer, and their functions aides the advancement of disease. It is known that overexpression of HSP70, a member of HSP family, in cancerous cells has been closely associated with tumor cell proliferation, apoptosis inhibition, enhanced migration and metastasis and drug resistance promotion. Therefore, targeting HSP70 in cancer treatment is very important. One of the best-studied inhibitors known for HSP70 is quercetin that is widely distributed flavonoid in the plant kingdom. Several in vivo and in vitro studies have reported the efficacy of quercetin in reducing elevated HSP70 levels in cancer therapy. It has become a focal point as an anticancer agent because of the induction of apoptosis in many different cancer cells. In this chapter, we reviewed the role of HSP70 in different cancer types and the suppressive effect of quercetin on expression of HSP70 family members. Moreover, we emphasized molecular mechanisms targeted by quercetin in cancer and its relationship to Hsp70.