A critical evaluation of the possibilities and limitations of the label-free detection of deoxyribonucleic acid (DNA) hybridization by means of field-effect-based devices is discussed. A new DNA-detection method is introduced, which utilizes an ion-sensitive field-effect device as transducer. The upon the DNA hybridization induced redistribution of the ion concentration within the intermolecular spaces and/or the alteration of the ion sensitivity of the device is proposed as detection mechanism. The theoretical calculations predict a substantial change in the average ion concentration within the intermolecular spaces induced upon hybridization that are enough to obtain a detectable sensor signal.