Hemostasis is the process to prevent bleeding and encompasses the interplay of endothelial cells in the vessel wall, platelets and plasma proteins. Hemostatic imbalance in one of these components can result in thrombosis or bleeding problems. Mass spectrometry based proteotyping has the potential to address the unmet clinical needs in biology-driven diagnosis of bleeding or thrombotic disorders, prediction of hemostatic events and therapy response monitoring. In our research studies, we use complementary proteomics and peptidomics approaches combined with differential mass spectrometry-based acquisition strategies to unravel molecular aetiologies underlying thrombotic or bleeding episodes. High-resolution Orbitrap MS platforms and TimsTOF MS technology empowered high-throughput profiling of the endothelial, platelet and plasma proteome. Based on this multi-proteomics approaches, we constructed a proteomic landscape of hemostatic disorders, including defects in primary hemostasis (platelet function disorders, Von Willebrand disease and endothelial dysfunction) and secondary hemostasis (coagulation factor deficiencies and bleeding disorders of unknown cause). Proteogenomic analysis of Von Willebrand factor proteoforms facilitated Von Willebrand Disease subclassification without a priori genotypic information. Peptidomics on coagulated plasma highlighted in-depth insights on proteolytic events in secondary hemostasis, including zymogen to enzyme transitions and regulation of serpin activity. Finally, within a framework of clinicians, clinical chemists and hemostasis experts, we designed a targeted proteomics assay for absolute quantification of coagulation and fibrinolysis proteins in harmonization with functional hemostatic assays of the clinical chemistry laboratory. In conclusion, our studies highlight the advances in multi-proteomics for molecular footprinting in bleeding and hemostasis.