The paper offers a survey on literature data on the very wide subject concerning the interaction of a particular class of polyphenols, flavonoids, with plasma proteins. Recent developments in applying fluorescence (steady-state, time-resolved, synchronous techniques), circular dichroism and vibrational (FTIR and Raman) spectroscopies for obtaining relevant parameters (binding constant, K, number of binding sites, thermodynamic effects) are presented. Attention is paid to the modifications occurring upon the interaction process in the secondary and tertiary protein structure, as well as in the ligand conformation. In this case, we underline the significant role played by analyzing the induced dichroic signals of the ligand forced to adopt a restricted conformation in the protein pocket. In order to better understand the molecular aspects of the binding process, the differences in experimental data are discussed in terms of the structural elements of flavonoids, namely the number and position of the OH groups, the presence of methoxy and glycosidic residues and the character of the C2-C3 bond in the A ring. Some correlations of logK with parameters such as the hydrophobicity, hydrogen bond donor and acceptor character, and polar surface are also discussed. In the last section we present the representative theoretical results obtained insofar on both isolated ligands (by DFT and TDDFT methods) and supramolecular ligand-protein systems (by molecular mechanics and dynamics).