For most evolutionary biologists, molecular evolution means “genes and proteins.”  This narrow focus neglects the critical roles played by evolution of the systems of small solutes — organic osmolytes, inorganic ions and protons — that establish the “working environment” for macromolecules. Study of adaptive modification of the types and concentrations of “micromolecules” in biological fluids provides deep insights into evolutionary processes in the context of adaptation to extreme environments and into the physiological changes that promote homeostasis.