AlGaN/GaN based pH-sensors have been characterized and further developed for the in situ monitoring of cell reactions. Generally, good proliferation of different cell lines was observed on AlGaN and GaN surfaces without using any kind of thin films of organic material for improving of the cellular adhesion and biocompatibility. NG108-15 nerve cells were chosen for the investigation of the sensor response on cell activity. In an open setup with contact to normal atmosphere, the monitoring of the spontaneous cell activity (“breathing”) was recorded. By titration in complex electrolytes, it was demonstrated that these sensors are able to monitor complex cell reactions on different neuroinhibitors. Numerical simulations as well as simplified analytical calculations of ion fluxes give strong evidence that the signal in the cell-transistor coupling experiments is primarily generated by the Na+ flux. In conclusion, the AlGaN/GaN-ISFETs show stable operation under physiological conditions, exhibit a very good signal resolution and are suitable for long-time monitoring of cell reactions on different stimuli.