As a zoologist, Hans H. Ussing began his scientific career by studying the marine plankton fauna in East Greenland. This brought him in contact with August Krogh at the time George de Hevesy, Niels Bohr and Krogh planned the application of artificial radioactive isotopes for studying the dynamic state of the living organism. Following his studies of protein turnover of body tissues with deuterium-labeled amino acids, Ussing initiated a new era of studies of transport across epithelial membranes. Theoretical difficulties in the interpretation of tracer fluxes resulted in novel concepts such as exchange diffusion, unidirectional fluxes, flux-ratio equation, and solvent drag. Combining methods of biophysics with radioactive isotope technology, Ussing introduced and defined the phrases ‘short-circuit current', ‘active transport pathway' and ‘shunt pathway', and with frog skin as experimental model, he unambiguously proved active transport of sodium ions. Conceived in his electric circuit analogue of frog skin, Ussing associated transepithelial ion fluxes with the hitherto puzzling ‘bioelectric potentials'. The two-membrane hypothesis of frog skin initiated the study of epithelial transport at the cellular level and raised new questions about cellular mechanisms of actions of hormones and drugs. His theoretical treatment of osmotic water fluxes versus fluxes of deuterium labeled water resulted in the discovery of epithelial water channels. His discovery of paracellular transport in frog skin bridged studies of high and low resistance epithelia and generalized the description of epithelial transport. He devoted the last decade of his scientific life to solute-coupled water transport. He introduced the sodium recirculation theory of isotonic transport, and in an experimental study, he obtained the evidence for recirculation of sodium ions in toad small intestine. In penetrating analyses of essential aspects of epithelial membrane transport, Ussing provided insights of general applicability and powerful analytical methods for the study of intestine, kidney, respiratory epithelia, and exocrine glands-of equal importance to biology and medicine.