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The paper describes a bioluminescence detection lab-on-chip consisting of a fiber-optic faceplate with immobilized luminescent reporters/probes that is directly coupled to an optical detection and processing CMOS system-on-chip (SoC) fabricated in a 0.18-μm process. The lab-on-chip is customized for such applications as determining gene expression using reporter gene assays, determining intracellular ATP, and sequencing DNA. The CMOS detection SoC integrates an 8 × 16 pixel array having the same pitch as the assay site array, a 128-channel 13-bit ADC, and column-level DSP, and is fabricated in a 0.18-μm image sensor process. The chip is capable of detecting emission rates below 10-6 lux over 30 s of integration time at room temperature. In addition to directly coupling and matching the assay site array to the photodetector array, this low light detection is achieved by a number of techniques, including the use of very low dark current photodetectors, low-noise differential circuits, high-resolution analog-to-digital conversion, background subtraction, correlated multiple sampling, and multiple digitizations and averaging to reduce read noise. Electrical and optical characterization results as well as preliminary biological testing results are reported.