Chemotherapeutic agents and radiation are established treatment modalities for many tumor types. However, the development of tumor resistance to therapy (chemoresistance and radioresistance) and non-specific toxicity toward normal cells remains a major obstacle. Most studies involving plant-derived polyphenols have focused on their potential chemopreventive properties but only relatively recently have many natural polyphenols been shown to sensitize tumor cells to chemotherapy and radiation through the inhibition of pathways that lead to treatment resistance. Notable examples include curcumin, genistein, resveratrol, caffeic acid phenethyl ester, flavopiridol, and green tea polyphenols. Furthermore, studies, suggest that plant polyphenols may also hold value in preventing or alleviating therapy-related side effects through pathways linked to inflammation.