Platelets are physiologically and metabolically active anucleate blood cells with central roles in hemostasis, inflammation, immune responses, and thrombosis. As dynamic sentinels of vascular homeostasis, platelet function is largely dictated by the complete repertoire of proteins expressed by platelets—the platelet proteome—which encompasses receptors, signaling molecules, metabolic enzymes, secretory factors, and cytoskeletal components. Over the past few decades, advances in mass spectrometry and proteomics technologies have enabled the systematic identification and quantification of more than 5,000 distinct platelet proteins, providing proteomic maps of platelet activation, secretion, and intracellular signaling pathways in health and disease. Proteomic approaches have revealed thousands of platelet protein variants (“proteoforms”) arising from alternative splicing, genetic polymorphisms, proteolytic processing, and post-translational modifications, particularly phosphorylation. Emerging methodologies, including “top-down” and single-cell proteomics, now hold promise for capturing platelet proteotype diversity and functional heterogeneity at unprecedented resolution. However, translating these proteomic insights into biomarkers, clinical applications, and deeper biological understanding remains a challenge due to inconsistencies in sample preparation and complexities in data interpretation and integration. This chapter provides an overview of platelet proteomics methodologies, historical advances, challenges in clinical translation, and future directions in leveraging proteomics to enhance models of platelet physiology, personalized medicine, and biomarker discovery.