Twenty-Five Years of High-Throughput Screening of Biological Samples with Mass Spectrometry: Current Platforms and Emerging Methods

Robust high-throughput screening (HTS) approaches for discovering new chemical entities are desirable for research and translation. Applications for which high-throughput (HT) methods are particularly required also include the screening of potential therapeutics for drug discovery and development, profiling of biofluids for disease biomarker discovery, and clinical diagnostics. Complementing the demand for HTS from specific application areas are substantial technological advancements in the fields of automation, microfluidics, and ambient ionization that facilitate highly automated and sophisticated analytical workflows. The time period spanning 2000–2025 has witnessed a significant expansion in the mass spectrometry (MS) capabilities and technology. This has included novel ionization approaches that can achieve rapid analysis with minimal solvent and sample consumption, while retaining high sensitivity and specificity in the absence of chromatography. Despite the demand for HTS methods and the well-documented analytical capabilities of MS, optical methods dominate as the HTS detection methods of choice. This perspective provides an overview of the evolution of HTS-MS over the last 25 years, focusing on emerging approaches that also provide efficient and sustainable workflows that compete with optical detection. Additionally, this perspective will highlight challenges in the field that may hinder widespread adoption and consider lessons from the COVID-19 pandemic, as well as the impact of sustainability on the future of HTS-MS and analytical chemistry.