The detection of chemical and biological species is critical for applications in healthcare, environmental monitoring, food safety and drug screening. Potentiometric biochemical sensors rely on the specific adsorption of charged analytes that changes the potential of the functionalized sensor surface. The change in surface potential can be measured using a field-effect-transistor enabling low-cost fabrication, and easy integration with portable readout electronics. Over the past several decades, these sensors have been demonstrated to detect pH changes, metal ions, DNA, biomarkers, proteins, and enzymes. Although many biosensing experiments have been reported, many of the results are not well understood and several key challenges are still limiting their widespread application. The ability to stabilize and control the attachment of cells on the sensor surface is critical. Therefore, the reliability and reproducibility of self-assembled-monolayers will be presented. The experimental response from a variety of sensor surfaces (oxides or metals) and transducers (conventional silicon, nanowire, extended gate, or graphene transistors) will be presented. The results show that the choice of the active interface in contact with the electrolyte determines the sensor response and selectivity (the signal) independent of the transducer. The choice of the readout transducer mainly influences the noise limit, and, hence, the signal-to-noise ratio. Models for diffusion, attachment, and electrical response of these sensors will be described that demonstrates good agreement to experimental data. Finally, the application of these devices in the animal health sector for the diagnosis of bovine respiratory disease, which is a major cause of calf death, will also be presented.