Miniaturization in High Throughput Screening (HTS) is perceived as essential by pharmaceutical screening laboratories to accommodate the enormous increase in compounds and targets over the past few years. The two primary goals are to increase throughput while decreasing costs. The ability to perform primary screening assays in high-density micro-well plates at volumes of 1-2µl will accelerate the early stages of drug discovery. Ultra-HTS (uHTS) assays require an accurate and reliable means of fluid handling in the submicroliter volume range. This relates to the design of instrumentation for dispensing fluids, as well as assay plates. Fluid handling has been a major obstacle to the full implementation of miniaturized assays. This report focuses on current approaches to submicroliter fluid handling in high-density multi-well plates.