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This paper reports on the design and evaluation of a high-throughput assay system for investigating the biological effects of microwave/millimeter wave radiation. The approach presented here differs significantly from others with the deployment of a continuous culture device and sample handling technology that allows the rapid presentation of test samples in a uniform physiological state. Segmented flow of the sample passes through a fundamental mode millimeter-wave exposure cell that is, in this prototype, well characterized between 26 and 40 GHz. A sensitive bioluminescence-based reporter monitored the temporal evolution in each assay segment using optical detector arrays mounted at three observation points, i.e., before the sample entered the cell and during millimeter-wave exposure and postexposure. Using this approach, the continuous monitoring of bioluminescence may be used on different time scales to measure cell energy metabolism, gene expression and growth. Exposed and control samples were monitored and any combination of stimulus parameters, namely, radiation frequency, intensity, and polarization (or any modulation of these) that induced a response that exceeded a noise threshold of the system could be further investigated automatically in real time, for example, with increased frequency resolution and at different power levels. Environmental parameters such as the temperature and magnetic and electric fields were carefully controlled. This sensitive “active” search system may have application in industry, biomedical research, and environmental health. © 2003 American Institute of Physics.