Studying the acid-base properties of protein molecules led us to reconsider the operational mechanism of ISFETs. Based on the site-dissociation model, applied to the amphoteric metal oxide gate materials used in ISFETs, the sensitivity of ISFETs is described in terms of the intrinsic buffer capacity of the oxide surface, ßs, and the electrical surface capacitance, Cs. The ISFET sensitivity towards changes in the bulk pH is fully described by the ratio ßs/Cs. Practical measurements support this theoretical approach. The new approach to the description of the acid-base properties of ISFETs is analogous to the classical description of the acid-base properties of protein molecules. The acid-base titration of proteins is also determined by the ration between the intrinsic buffer capacity and the electrical double layer capacitance. In addition to the amazing conclusion that ISFET surfaces and protein molecules behave in a similar way with respect to their acid-base properties, further conclusions are drawn with respect to the possibility of protein characterization by means of dynamic measurements with protein covered ISFETs. Design rules are given for this type of biosensors, based on the theoretical understanding of the acid-base behaviour of both sensor parts.