Organic osmolytes are small solutes used by cells of numerous water-stressed organisms and tissues to maintain cell volume. All known osmolytes are amino acids and derivatives, polyols and sugars, methylamines, and urea; unlike salt ions, most are “compatible,” i.e., do not perturb macromolecules. In addition, some stabilize macromolecules and are “counteracting” towards perturbants, e.g., methylamines can stabilize proteins and ligand binding against perturbations by urea in elasmobranchs and mammalian kidney, and (our latest findings) high hydrostatic pressure in deep-sea animals. Methylamines appear to coordinate water molecules tightly, resulting in osmolyte exclusion from hydration layers of peptide backbones. This makes unfolded protein conformations entropically unfavorable (work of Timasheff, Galinski, Bolen and coworkers). These properties have led to proposed uses in biotechnology, agriculture and medicine, including improved biochemical methods, in vitro rescue of misfolded proteins in cystic fibrosis and prion diseases (work of Welch and others), and plants engineered for drought and salt tolerance. These properties also explain some but not all of the considerable variation in osmolyte composition among species with different metabolisms and habitats, and among and within mammalian tissues in development.