ABSTRACT The High-Throughput Screening (HTS) Core (Core A) carries out target- and phenotype-based screens of small-molecule libraries. The HTS core will directly support the activities of more than ten CF-related screening projects, including correctors and potentiators for rare CFTR mutations such as N1303K, W1282X and c.3700A>G, as well as several additional ion transport targets, including SLC26A gene family members, that are relevant to pulmonary and non-pulmonary CF indications. The instrumentation available for screening includes a fully automated screening platform with liquid handling and two plate readers, and multiple separate plate readers some with stackers. Plate-readers provide fluorescence, polarization, absorbance, and luminescence readout. Functions of Core A include compound storage and handling, assay design and validation, assay execution, and data analysis. Core A resources also include HPLC, LC/MS, and NMR instrumentation for compound quality control. Core A also carries out optimization of validated initial `hits' (active compounds) by screening commercially available analogs. Further `hit-to-lead' development is done on individual projects in consultation with the Chemistry Core (Core C). Having operated Core A for the past 14 years, the Core has established practical procedures for efficient and cost-effective compound screening, quality control, and hit-to-lead optimization.