Tannins are a heterogenous class of polyphenolic natural products with promising cancer chemopreventive and therapeutic potential. Studies undertaken over the last 30 years have demonstrated their capacity to target many cellular pathways and molecules important in the development of cancer. Recently, new mechanisms that might be important in anti-carcinogenic activity, such as inhibition of epithelial-to-mesenchymal transition, reduction of cancer stem cell creation, and modulation of cancer cells metabolism have been described. Along with the mechanisms underlying the anti-cancer activity of tannins, this review focuses on their possible application as chemosensitizers in adjuvant therapy and countering multidrug resistance. Furthermore, characteristic physicochemical properties of some tannins, particularly tannic acid, are useful in the formation of nanovehicles for anticancer drugs or the isolation of circulating cancer cells. These new potential applications of tannins deserve further studies. Well-designed clinical trials, which are scarce, are needed to assess the therapeutic effects of tannins themselves or as adjuvants in cancer treatment.