Long a prized analytical tool for low and medium-throughput applications, recent innovations in mass spectrometry (MS) are changing the way pharmaceutical scientists apply MS to challenges requiring truly high-throughput. Such endeavours include HTS, parallel medicinal chemistry and protein engineering with emerging needs in drug metabolism and pharmacokinetics as well. At Merck, we have embarked on a journey to incorporate these innovative uHT-MS capabilities in our own approach to drug discovery. This presentation will highlight how we have deployed both a fully-automated uHT-MALDI-MS instrument and the Echo-MS platform in a cross-functional research setting. As one example, we will demonstrate application of the uHT-MALDI-MS to a prototypical HTS assay for a kinase target. Here we will discuss how we have enabled ‘on-demand’ MALDI target plate preparation in both 384w and 1536w formats and will further compare & contrast this data to those obtained using a conventional Glo assay for both primary (single concentration) screening and compound titrations. We will also describe how we have leveraged the Echo-MS platform to triage hits from an HTS designed to discover inhibitors of lipid metabolism which employed a fluorescent, cell-free assay. Here, we will highlight a useful “quench-and-read” sample preparation approach that allows for the selective enrichment of hydrophobic analytes and which is also fully compatible with direct acoustic transfer of the surface solution to the mass spectrometer for analysis. Throughout the presentation we will highlight the relevant figures of merit for each application and discuss our findings around the ‘critical parameters’ whose optimization was important to enabling assay success. Finally, we will conclude with a perspective of the future of our journey in this space.