The structure and dynamics of proteins in solution are closely related to their activity and, ultimately, to their performance in products and technologies, for example, drug formulations and enzymatic catalysis. With this in mind, the study of the fundamental behavior of proteins in deep eutectic solvents not only provides insight into a novel alternative to aqueous and molecular organic solvents, but also contributes to understanding the potential behavior of these macromolecules in non-aqueous environments. In particular, it has relevance for systems with high levels of dehydration, liquid phases for dispersions at cryogenic temperatures, or systems with high ionic strength. In this chapter, we will explore current knowledge of the physicochemical behavior of proteins in deep eutectic solvents. The local and global structure of proteins in these solvents will be presented and compared to those in aqueous solutions, organic solvents and ionic liquids. Furthermore, the characteristic behavior of proteins in deep eutectic solvents will be linked to solvation effects and the interaction of the macromolecules with the solvent, where specific electrostatic and hydrogen bond interactions can affect the structure and dynamics of proteins. Finally, challenges and opportunities in the field will be discussed, with the aim of guiding a common effort to develop a better understanding of the fundamental behavior of proteins in these interesting environments.