Accurate biomarkers are a crucial and necessary precondition for precision medicine, yet existing ones are often unspecific and new ones have been very slow to enter the clinic. Mass spectrometry (MS)-based proteomics excels by its untargeted nature, specificity of identification, and quantification, making it an ideal technology for biomarker discovery and routine measurement. It has unique attributes compared to affinity binder technologies, such as OLINK Proximity Extension Assay and SOMAscan. In in a previous review in 2017, we described technological and conceptual limitations that had held back success. We proposed a 'rectangular strategy' to better separate true biomarkers by minimizing cohortspecific effects. Today, this has converged with advances in MS-based proteomics technology, such as increased sample throughput, depth of identification, and quantification. As a result, biomarker discovery studies have become more successful, producing biomarker candidates that withstand independent verification and, in some cases, already outperform state-of-the-art clinical assays. We summarize developments over the last years, including the benefits of large and independent cohorts, which are necessary for clinical acceptance. Shorter gradients, new scan modes, and multiplexing are about to drastically increase throughput, cross-study integration, and quantification, including proxies for absolute levels. We have found that multiprotein panels are inherently more robust than current single analyte tests and better capture the complexity of human phenotypes. Routine MS measurement in the clinic is fast becoming a viable option. The full set of proteins in a body fluid (global proteome) is the most important reference and the best process control. Additionally, it increasingly has all the information that could be obtained from targeted analysis although the latter may be the most straightforward way to enter regular use. Many challenges remain, not least of a regulatory and ethical nature, but the outlook for MS-based clinical applications has never been brighter.