Abstract The sections in this article are: What Makes a Solute an Osmolyte? The Basic Osmoregulatory Response: Conservation Paired with Change Osmolyte Taxonomy: Evolutionary Convergence and Conservation The Discovery of Organic Osmolytes Polyols and Sugars Free Amino Acids and Their Derivatives Methylated Ammonium and Sulfonium Compounds Urea and Urea with Methylamines Osmolyte Effects: Perturbation, Stabilization, and Compatibility Changes in Concentrations of Inorganic Ions Are Generally Perturbing of Biochemical Systems Organic Osmolyte Compatibility with Biochemical Functions In Vitro Organic Osmolyte Compatibility with Protein Structure In Vitro Compatibility of Organic Osmolytes: In Vivo and Cell Culture Studies Organic Osmolyte Effects: Counteracting Solute Systems Counteracting Solute Effects In Vitro Urea Counteraction in Living Systems Salt Counteraction (Haloprotection) Exceptions to Counteraction Regulation of Osmolyte Concentrations Interspecific Similarities in Basic Regulatory Strategies Osmolyte Regulation in Bacteria and Plants Osmolyte Regulation in Invertebrates Osmolyte Regulation in Lower Vertebrates The Mammalian Kidney Stress Protein Induction in Hyperosmotic Stress Mechanisms of Solute Effects—and Non‐Effects The Hofmeister Series and Organic Osmolyte Structures Preferential Exclusion of Compatible Osmolytes from the Protein Surface Solute Interactions with Ligands in Solution Nonreactivity of Modified Amino Acid Osmolytes Monosaccharide Reactivity with Proteins Favorable Effects of Compatible Solutes Not Related to Osmoregulation Inorganic Ions: Perturbation and Compatibility Evolutionary Perspectives Macromolecular vs. “Micromolecular” Evolution Evolution of Osmolyte Molecules: An Overview of Principles of Selection Summary: The Adaptive Significance of Osmolyte System Evolution