The search for green solvents that can replace harsh organic solvents and relatively toxic ionic liquids (ILs) has led to the discovery of deep eutectic solvents (DES). DES are now rapidly emerging in numerous applications owing to their green character, biodegradability, tuneability, low cost and simple preparation, compared to other solvents. The possibility that natural DES might play a role as an alternative media to water in living organisms pushed the researchers to investigate their use as solvents for the poorly water soluble macromolecules. However, the addition of water in most of their applications must be controlled to maintain DES' supramolecular structure and properties. This review presents the impact of water on DES, used as solvents for the biological macromolecules mainly phospholipids, proteins, nucleic acids and polysaccharides. The effect of water on the DES' supramolecular network and its physico-chemical properties is discussed and the applications of DES as solvents for the biological macromolecules, in the absence and presence of water, are highlighted.