The ability to accumulate polyphenols with light absorbance allowed early land plants to resist UV irradiation and made survival on land possible. Largely consumed, polyphenols are not synthesized by human being. Present only in plants and some microorganisms, the number of described phenolic compounds (over 8000), is increasing due to the continual evolution of new genes and mutations in response to the adaptation to environmental changes. A wide range of biological studies revealed the antioxidant properties of polyphenols towards human pathologies such as cancer. The health benefits of polyphenols, however, depend on their amount ingested and on their bioavailability. Many factors have great influence on bioavailability of polyphenols such as the climate, agricultural practices, industrial processes and the host microbiota considered to act as a metabolic organ with an important role in human metabolism. The polyphenols anticancer effect relies on their chemical structure, concentration and on the type of cancer. The biological activity of polyphenols has been extensively studied in preclinical assays. Some polyphenols can overcome cancer chemotherapeutic resistance by modulating cancer cells with multiple drug resistance (MDR) overexpression phenotype. In solid tumours and hematological malignances, polyphenols, exert an important role in apoptosis induction, cell growth inhibition, cell cycle arrest, oxidative stress, and in cell migration and differentiation. The combination of flavonoids and chemotherapy seems to be an interesting approach for cancer treatment. In addition, some points related to the polyphenols bioavailability and delivery needs to be elucidated in order to improve their biological effects in vivo.