We present a highly sensitive chemical sensor system including a chip with an array of silicon nanowire ISFETs and a CMOS chip with custom-designed signal-conditioning circuitry. The CMOS circuitry, comprising 8 sigma-delta (Sigma-Delta) modulators and 8 current-to-frequency converters, has been interfaced to each of the nanowires to apply a constant voltage for measuring the respective current through the nanowire. Each nanowire has a dedicated readout channel, so that no multiplexing is required, which helps to avoid leakage current issues. The analog signal has been digitized on chip and transmitted to a host PC via a FPGA. The system has been successfully fabricated and tested and features, depending on the settings, noise values as low as 8.2 pA(RMS) and a resolution of 13.3 bits while covering an input current range from 200 pA to 3 mu A. The two readout architectures (Sigma-Delta and current to frequency) have been compared, and measurements showing the advantages of combining a CMOS readout with silicon nanowire sensors are presented: (1) simultaneous readout of different silicon nanowires for high-temporal-resolution experiments and parallel sensor experiments (results from pH and KCl concentration sweeps are presented); (2) high speed measurements showing how the CMOS chip can enhance the performance of the nanowire sensors by compensating its non-idealities as a consequence of hysteresis. (C) 2014 Elsevier B.V. All rights reserved.