Polyphenols, plant secondary metabolites, are present in human diet and have been widely used for medical and cosmetic purposes. They possess beneficial features such as antioxidant, immunomodulatory, anti-cancer and antibacterial activity. There is some evidence that these phytochemicals can improve wound healing. However, more and more data suggest that, under certain conditions, they can act in a different, often unpredictable way. Some investigations indicate that polyphenols, generally known as antioxidants, can exhibit pro-oxidant, and therefore cytotoxic, activity. Hence, the ability of phytochemicals to induce apoptosis of cancer cells and bacterial cell damage may be, at least partly, due to their prooxidant properties. Phytocompounds enter the body through the digestive system where they undergo metabolic processes that often change their chemical features. The gastrointestinal microbiome interacts with phytochemicals and influences their bioavailability and absorption in the gut. Except for biochemical changes of plant polyphenols in the host, the achievement of therapeutic concentration in vivo may be the main problem in the determination of their real efficacy. Ambiguous results of some studies demonstrate the need for the development of more accurate and standardized methods for the evaluation of polyphenols' properties. Better understanding of human body-polyphenol interactions is crucial for more effective use of these phytochemicals in disease prevention and therapy.