Non-targeted metabolomics by mass spectrometry has established as the method of choice for investigating metabolic phenotypes in basic and applied research. Compared to other omics, metabolomics provides broad scope and yet direct information on the integrated cellular response with low demand in material and sample preparation. These features render non-targeted metabolomics ideally suited for large scale screens and discovery. Here we review the achievements and potential in high-throughput, non-targeted metabolomics. We found that routine and precise analysis of thousands of small molecular features in thousands of complex samples per day and instrument is already reality, and ongoing developments in microfluidics and integrated interfaces will likely further boost throughput in the next few years.