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In cell biology research, the scale of the system limits the utilization of traditional electroanalytical microsensors to study the biological activity of single cells. The application of electroanalytical microsensors to this research can be broadened by developing new technologies. This includes the application of the principles of the vibrating (self-referencing) ion-selective microelectrode to the operation of these types of sensors. This involves fabrication and testing of advanced electroanalytical microsensors, and the development of a self-referencing electroanalytical microelectrode (SREM) instrumentation platform. SREM sensors have been developed for analytes such as oxygen, nitric oxide, and ascorbic acid (vitamin C). All of these sensors have demonstrated a high level of sensitivity and spatial resolution. This approach has been validated against nonbiological microscopic flux sources that were theoretically modeled before being applied to isolated single cells. These new sensor technologies have been shown, through research in a wide variety of biological and biomedical research projects, to be an important new tool in the arsenal of the cell biologist. Recently this SREM technology has also been adapted through the development of SREM-H2O2 and SREM-NADH sensors to support the use of electrochemically coupled enzyme based biosensors. Based on this self-referencing biosensors (SRB) for glucose and ethanol have been developed and have undergone validation testing in artificial systems. These developments in self-referencing sensor technologies offer great promise in extending the application of electroanalytical and biosensor technologies from the micro to the nanoscale.