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Abstract Protein solubility and stability depend on the co-solutes present. There is little theoretical basis for selection of suitable co-solutes. Some guidance is provided by the Hofmeister series, an empirical ordering of anions according to their effect on solubility and stability; and by osmolytes, which are small organic molecules produced by cells to allow them to function in stressful environments. Here, NMR titrations of the protein barnase with Hofmeister anions and osmolytes are used to measure and locate binding, and thus to separate binding and bulk solvent effects. We describe a rationalisation of Hofmeister (and inverse Hofmeister) effects, which is similar to the traditional chaotrope/kosmotrope idea but based on solvent fluctuation rather than water withdrawal, and characterise how co-solutes affect protein stability and solubility, based on solvent fluctuations. This provides a coherent explanation for solute effects, and points towards a more rational basis for choice of excipients.