Motivated by the design of an integrated CMOS-based detection platform, a simulation model for CCD and CMOS imager-based luminescence detection systems is developed. The model comprises four parts. The first portion models the process of photon flux generation from luminescence probes using ATP-based and luciferase label-based assay kinetics. An optics simulator is then used to compute the incident photon flux on the imaging plane for a given photon flux and system geometry. Subsequently, the output image is computed using a detailed imaging sensor model that accounts for photodetector spectral response, dark current, conversion gain, and various noise sources. Finally, signal processing algorithms are applied to the image to enhance detection reliability and hence increase the overall system throughput. To validate the model, simulation results are compared to experimental results obtained from a CCD-based system that was built to emulate the integrated CMOS-based platform.