Oligonucleotide-modified surfaces are at the core of microarray and biosensor technologies in which the ability of surface-tethered DNA “probes” to bind complementary nucleic acid “target” molecules in solution is the key element. The efficiency of this binding event is lessened to a large extent by electrostatic repulsions between the immobilized chains and the like-charged analyte strands in solution. We compare surface hybridization behavior of charged (DNA) with that of charge-neutral (DNA analogue) probes. Hybridization of nucleic acid targets to uncharged probes readily proceeds under low ionic strength conditions when DNA probes fail to react. However, electrostatics retains an important role because surface charge is introduced by bound targets, which act to limit the extent of hybridization. In addition to an enhanced binding affinity, use of uncharged probes bestows benefits from a diagnostic perspective. Perhaps the most significant advantage is that uncharged probes do not screen electrostatic interactions of targets with the solid support, thus allowing for sensitive transduction of probe-target binding with electrostatic techniques even when similar methods fail with charged probes.