This paper reviews the development in the 1950s of methods to determine the redox states of the free [NAD+]/[NADH] in cytoplasm of yeast by Helmut Holzer and Feodore Lynen and in rat liver by Theodore Bucher and Martin Klingenberg. This work was extended in the 1960s in the laboratory of Hans Krebs, where the use of basic thermodynamic and kinetic principles allowed the extension of this approach to the determination of the free mitochondrial [NAD+]/NADH] in mitochondria and the redox state of the free NADP system in cytoplasm and mitochondria. This work also outlined the linkage between the redox states in the various couples to the phosphorylation state or the free [ATP]/[ADP][Pi] ratio, the central energy parameter of living cells. This work has since been extended to include other energy-linked systems including the gradients of inorganic ions between extra and intracellular phases of the cell and the redox state of the co-enzyme Q couple of mitochondria. This system of linked near-equilibrium redox and phosphorylation potentials constitutes a framework of primitive metabolic control that is altered in a number of disease phenotypes. The alteration of such disease phenotypes by substrate availability is discussed, as well as the importance of a thorough grounding in basic kinetics and thermodynamics in designing new therapies to normalize the metabolic abnormalities that are the proximate cause of many common and some rare diseases states.