Non-covalent and covalent associations of polyphenols with food macromolecules are two of the most fundamental factors affecting the quality of polyphenol-rich food products. This review therefore describes the biochemical bases of associations between polyphenols and macromolecules, that is, proteins and polysaccharides. Our intent is to provide a level of understanding that can be used to underpin future research directions. This will help to resolve existing issues that limit organoleptic and nutritional qualities of polyphenol-rich foods and drinks. It will also allow a better understanding of the functional consequences of these interactions on food/biological systems. The methods used to study non-covalent and covalent interactions are described, and the limiting factors of each method are emphasized. The biochemical mechanisms of interaction between polyphenols and macromolecules are also described. In processed food, non-covalent polyphenol/macromolecule interactions are largely due to weak associations, and result from a combination of hydrogen bonds and hydrophobic interactions. The biochemical mechanisms for covalent interactions involve oxidation of phenolic compounds, whether enzymatically mediated or not, with the formation of o-quinones or o-semi-quinones, or the cleavage of procyanidin interflavanic bonds in acid medium with the formation of carbocations. The effects of factors such as polyphenol structure, macromolecule structure, relative concentrations of both polyphenol and macromolecule, solvent composition, ionic strength, temperature, and pH are discussed.