Numerous cellular cosolutes significantly impact the way that proteins and other biomacromolecules act and interact. We have followed the thermodynamic effect of several cosolute classes, including polymers, cellular osmolytes, and inorganic salts, on the stability of biomolecular folding and complexation. By comparing changes in free energy, enthalpy, and entropy upon cosolutes addition for these processes, we identify several thermodynamically distinct mechanisms. Surprisingly, even while many cosolutes display similar scaling of the change in stabilizing free energy with their concentration, a breakdown of this free energy into enthalpic and entropic contributions distinguishes different families of cosolutes. We discuss how these “thermodynamic fingerprints” can direct towards possible underlying mechanisms that govern the cosolute effect.