We have developed a new fluorescence polarization (FP) reader suitable for high-throughput screening (HST) and ultra-HTS whose assay-performance and sample-throughput are both considerably improved over present state-of-the-art instrumentation. The SymmetryTM reader possesses a number of features that differ from conventional HTS FP readers. These include: laser-based excitation, liquid crystal polarization optics that rapidly and accurately measure polarization states; and CCD detectors to capture emission from multiple wells. We show that the performance in assays relevant to the drug discovery process, such as G- protein coupled receptor-based assays, is significantly enhanced due to a dramatic improvement in precision. Furthermore, the CCD-detection system used can substantially improve sample throughput compared to sequential readers while maintaining high performance.