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Over the past decade, ion-sensitive field-effect transistors (ISFETs) have played a major role in enabling the fabrication of fully integrated CMOS-based chemical sensing systems. This has allowed several new application areas, with the most promising being the fields of ion imaging and full genome sequencing. This paper reviews the new trends in front-end topologies toward the design of ISFET sensing arrays in CMOS for these new applications. More than a decade after the review of the ISFET by Bergveld which summarized the state of the art in terms of device and early readout circuity, we describe the evolution in terms of device macromodel and identify the main sensor challenges for current designers. We analyze the techniques that have been reported for both ISFET instrumentation and compensation, and conclude that topologies are focusing on device adaptation for offset and drift cancellation, as …