We offer a comprehensive theory of pH response of a coupled ISFET sensor to show that the maximum achievable response is given by ΔV/ΔpH = 59 mV/pH × α, where 59 mV/pH is the intrinsic Nernst response and α an amplification factor that depends on the geometrical and electrical properties of the sensor and transducer nodes. While the intrinsic Nernst response of an electrolyte/site-binding interface is fundamental and immutable, we show that by using channels of different materials, areas, and bias conditions, the extrinsic sensor response can be increased dramatically beyond the Nernst limit. We validate the theory by measuring the pH response of a Si nanowire-nanoplate transistor pair that achieves >10 V/pH response and show the potential of the scheme to achieve (asymptotically) the theoretical lower limit of signal-to-noise ratio for a given configuration. We suggest the possibility of an even larger pH response based on recent trends in heterogeneous integration on the Si platform.