High throughput screening (HTS), an industrial effort to leverage developments in the areas of modern robotics, data analysis and control software, liquid handling devices, and sensitive detectors, has played a pivotal role in the drug discovery process, allowing researchers to efficiently screen millions of compounds to identify tractable small molecule modulators of a given biological process or disease state and advance them into high quality leads. As HTS throughput has significantly increased the volume, complexity, and information content of datasets, lead discovery research demands a clear corporate strategy for scientific computing and subsequent establishment of robust enterprise-wide (usually global) informatics platforms, which enable complicated HTS work flows, facilitate HTS data mining, and drive effective decision-making. The purpose of this review is, from the data analysis and handling perspective, to examine key elements in HTS operations and some essential data-related activities supporting or interfacing the screening process, and outline properties that various enabling software should have. Additionally, some general advice for corporate managers with system procurement responsibilities is offered.