Simple SummaryThe ability of chemical denaturants to perturb protein structures is well-established, but the physico-chemical basis underlying this phenomenon is still debated. In the present review, we survey classical and recent literature to provide a global overview of the effects that chemical denaturants produce on the different structural states of proteins, from globular to intrinsically disordered and amyloid-like assemblies. Interestingly, the different forces that stabilize these distinct structural states generate intriguing effects. Even the ranking of the relative strength of the most common denaturants (i.e., urea and guanidinium ion), which is well-established and generally conserved for globular proteins, is not fully suited for other structural states. Analysis of available data, using both polymer physics and atomic-interaction-based perspectives, provides complementary and somehow convergent views of the mechanism of action of chemical denaturants. The different “quality” of water as a solvent in distinct contexts, and the remarkable promiscuity of chemical denaturants represent useful conceptual frameworks to shed light on these intricate phenomena.AbstractProteins perform their many functions by adopting either a minimal number of strictly similar conformations, the native state, or a vast ensemble of highly flexible conformations. In both cases, their structural features are highly influenced by the chemical environment. Even though a plethora of experimental studies have demonstrated the impact of chemical denaturants on protein structure, the molecular mechanism underlying their action is still debated. In the present review, after a brief recapitulation of the main experimental data on protein denaturants, we survey both classical and more recent interpretations of the molecular basis of their action. In particular, we highlight the differences and similarities of the impact that denaturants have on different structural classes of proteins, i.e., globular, intrinsically disordered (IDP), and amyloid-like assemblies. Particular attention has been given to the IDPs, as recent studies are unraveling their fundamental importance in many physiological processes. The role that computation techniques are expected to play in the near future is illustrated.