Protein folding in the cell is a tightly regulated process, involving a series of proteins, from molecular chaperones to proteases that assist the folding process and monitor the quality of the final product. Despite this control, genetic or sporadic factors may compromise protein folding and the folded state resulting in the formation of non-native misfolded, destabilised, aggregated or fibrillar species. These are hallmarks of the so-called protein conformational disorders, in which the altered protein conformations result in cell toxicity, functional deficiency or lead to dominant negative effects. Examples of such pathologies include neurodegenerative and metabolic disorders. In recent years, it has become clear that several different small chemical compounds such as osmolytes, protein inhibitors, ligands and cofactors exert a chemical chaperoning effect and are able to rescue folding and trafficking defects, minimising or partly overcoming the pathological consequences of protein misfolding. Here we review the different types of chemical chaperones and provide a structural and energetic rationale for their action. Examples of chemical chaperoning are overviewed and discussed on the basis of the reported effects exerted by chemical compounds at different stages of the protein folding process and protein conformational states.