The prevalence of metabolic disorders (MDs), especially diabetes, is rapidly increasing worldwide, leading to an increasing risk of cardiovascular and other socially relevant complications. To boost MD biomarker discovery, advanced proteomics can harmonize metabolomics. Indeed, the rapid development of mass spectrometry (MS) has designated proteomics as an emerging platform to interrogate the plasma/serum proteome for the discovery of next-generation biomarkers exploitable for risk assessment, early detection and prognosis of MDs. Preanalytical plasma/serum treatment, such as combinatorial peptide ligand libraries with nano-liquid chromatography coupled with tandem MS or selected reaction monitoring coupled to triple-quadrupole time-of-flight instruments, are proven clinical laboratory techniques for quantitative analyses. New strategies, such as SWATH™ MS, which allows us to systematically characterize and quantify query sample sets of 'any protein of interest' in complex biological samples, may dramatically improve next-generation MD biomarkers, especially considering the plethora of candidates coming from the 'bioreactor' gut microbiota affecting MD onset and progression.