A ChemFETs source and drain are constructed as for an ISFET, with the gate electrode separated from the source electrode by a solution. The gate electrodes interface with the solution is a semi-permeable membrane containing the receptors, and a gap to allow the substance under test to come in contact with the sensitive receptor moieties. A ChemFET's threshold voltage depends on the concentration gradient between the analyte in solution and the analyte in contact with its receptor-embedded semi-permeable barrier.
Often, ionophores are used to facilitate analyte ion mobility through the substrate to the receptor. For example, when targeting anions, quaternary ammonium salts (such as tetraoctylammonium bromide) are used to provide cationic nature to the membrane, facilitating anion mobility through the substrate to the receptor moieties.