Intrinsically Disordered Proteins (IDPs) are inherently sensitive to their chemical environment. For IDPs, the lack of a stable structure combined with their high solvent accessibility makes their ensemble more sensitive to physicochemical changes than folded domains. A biological context in which IDPs encounter massive alterations to the intracellular environment is desiccation (extreme drying). Desiccation leads to dramatic changes in the intracellular chemistry, both because of changing water levels and because desiccation-tolerant organisms enrich key cosolutes like trehalose and sucrose, in addition to IDPs, to counteract drying. Cosolutes, like trehalose, are known in a few cases to augment the protective function of IDPs, resulting in synergistic protection. However, the prevalence of synergy between IDPs and cosolutes during drying, its specificity, and the mechanism behind this synergy remain elusive. In this dissertation, I explore the idea that IDPs’ conformational ensemble and protective functions are tuned by known changes in the endogenous cosolute environment that occur during desiccation. Using representative proteins from three different IDP families, we show that IDPs synergize with their endogenous cosolutes to mediate desiccation protection. However, no concomitant change in the IDP ensemble was observed. We further show that synergy is driven by distinct molecular mechanisms depending on the class of the protectant. Our results demonstrate that organisms may have evolved to create a specific chemical environment to tune the function of constituent IDPs. Beyond desiccation tolerance, our finding provides evidence that the changing solution chemistry modulates IDP function and offers novel insights into the interplay between IDPs and their chemical environment.