The intermolecular and intramolecular non-statistical distribution of the isotopes of the bio-elements in natural compounds must obviously be controlled by logical principles. However, a critical review of the available isotope patterns of natural compounds indicates that a previously discussed general thermodynamic order and its mechanistic foundation cannot satisfactorily explain all experimental data. In the present contribution it is shown that a partial thermodynamic order can eventually be attained for defined positions and compounds under steady-state conditions of metabolism. However, as biological systems are generally open and irreversible, many other in vivo isotope discriminations are dominated by kinetic isotope effects, even in context with reversible reactions. On the other hand, kinetic isotope effects can only become effective in vivo in combination with metabolic branching and the implied isotope shifts of the products are balanced by their relative yields. In vivo, the influences of thermodynamic and kinetic isotope effects are modulated by interferences of the actual metabolic conditions, such as the nature and kind of precursors, alternative metabolic pathways, metabolite pools and fluxes, and by reaction mechanisms. This is demonstrated by giving examples for the isotopes of hydrogen, carbon, nitrogen, oxygen and sulfur, while simultaneously the particularities of the individual elements are elaborated. The resulting general theory of the origin of non-statistical isotope distributions in biological systems permits the interpretation and prediction of isotope patterns and provides the scientific basis for the elucidation of biosyntheses and origin assignments of natural compounds.