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Histone deacetylases (HDACs) regulate many important physiological processes and the discovery of small molecules that modulate HDAC activity has both academic and clinical relevance. HDAC inhibitors, most notably SAHA, have been pursued as cancer chemotherapeutics but may be useful in treating psychiatric disorders, malaria, and other diseases. Herein, we describe an inexpensive and robust assay, based on fluorescence polarization, for HDAC ligand discovery. The assay is well suited for high-throughput screening and enzyme kinetic studies.