Systems Biology and ‘Omics' require reproducible identification and quantitation of many compounds, preferably in large sample cohorts. Liquid chromatography-mass spectrometry is important since data generated can be used for structure elucidation and highly specific targeted quantitation. Despite great success, the technique has limitations such as: compound coverage in one analysis, method development time and single sample analysis time which determines throughput. New instrument capabilities have led to improved methods, including ‘Data Independent Acquisition' so-called because acquisition is not changed by acquired data. SWATH-MS is a specific example that has quickly become prominent in proteomics because of increased peptide coverage, high quantitation accuracy, excellent reproducibility and the generation of a ‘digital map'. These capabilities are important in small molecules analyses although uptake in these applications has been slower. We describe the SWATH-MS technique, review its use in applications such as metabolomics and forensics, and summarize on-going improvements and future prospects.