Solvent flow generated during iontophoresis can be used to convect neutral molecules through the skin, thereby greatly enhancing their flux. This concept was exploited to realize noninvasive glucose measurement by its iontophoretic extraction from the subcutaneous tissue. The hypothesis was tested in vitro using hairless mouse skin. The dermal surface was bathed with a glucose solution; chambers on the epidermal surface housed the current delivery electrodes. Iontophoresis (at 0.36 mA/cm2) was performed for 2 hr, at the end of which the solutions in contact with the electrodes were analyzed. The amount extracted was proportional to the glucose solution concentration bathing the dermis. Higher radioactivity levels were found at the anode than at the cathode, possibly because of glucose metabolism during its outward transport across the skin. Glucose biotransformation results in negatively charged metabolites which migrate to the anode. Two sensitive glucose sensors were developed; one was selective for glucose, the other for glucose and related compounds. Both sensors indicated the presence of glucose at the cathode but an abnormally high value was also recorded at the anode. This signal, however, was not due to glucose but rather to electroactive ascorbate withdrawn from the skin. Finally, a system has been developed with which glucose can be extracted noninvasively from the subcutaneous tissue and unambiguously measured. Whether iontophoretic glucose sampling in vivo will be equally suc-cessful remains to be answered.