Selective electron transfer reactions provide many opportunities for improving the performance of electrochemical detectors. Self-assembled alkanethiolate monolayers on gold are selective for derivatized ferrocenes (FcX) over ferrocyanide (Fe(CN)(6)(4-)). These interfaces faces enable redox recycling of FcX, a process that regenerates the analyte through a homogeneous electron transfer involving Fe(CN)6 as a strongly, but not fully blocked sacrificial electron donor. Although the anodic current for FcX is enhanced using this scheme, the level of background current can also increase due to the low-level electrolysis of Fe(CN)(6)(4-). This work investigates the characteristics of selectivity with respect to heterogeneous electron transfer kinetics and its impact on the limit of detection. To this end, digital simulations are used to construct a kinetic selectivity zone diagram for two redox couples. These zones demonstrate how the differences in the heterogeneous electron transfer rate constants, as expressed by a selectivity ratio, can be exploited to maximize performance. The interplay between various levels of selectivity and amplification is explored, including the effect of the relative concentrations and formal reduction potentials of the two species on the apparent selectivity. A mathematical model is developed to relate the voltammetric sweep rate, applied potential, concentration, and electrolysis rate of the sacrificial species to the signal to background ratio. These results demonstrate a direct relationship between selectivity and the improvement in the detection limit that can be achieved. Moreover, the two couples should be approximately thermoneutral, the optimal concentration of the sacrificial species is in the low millimolar range, and the applied potential should be as close to the reversible peak potential as possible. In some cases, the voltammetric sweep rate can be increased to improve selectivity and therefore sensitivity. The insights herein provide a basis for further improvements of system performance and enable facile evaluation of prospective amplification systems. (c) 2006 Elsevier B.V. All rights reserved.