It is increasingly recognized that platelets are the culprit cells implicated in the propensity to atherothrombosis in the setting of both type 1 and type 2 diabetes mellitus (T2DM), making the study of platelet pathophysiology and platelet activation/inhibition some of the most intriguing fields of research related to diabetes vascular complications. Indeed, a platelet hyper-reactive phenotype with biochemical evidence of persistent in vivo platelet activation, with enhanced thromboxane (TX) biosynthesis, has been described in diabetic patients in different stages along the natural history of the impairment of glucose metabolism, even in the preclinical phases. This chapter highlights several issues within this field: (1). the variable contribution of sustained and acute hyperglycemia, glycemic instability and insulin resistance to the observed changes in the platelet pathophysiology; (2). the role of oxidative stress and inflammation, and namely of platelet-derived inflammatory molecules and extracellular vesicles, as secondary mediators of diabetes-induced platelet activation; and (3). the complex intertwining between the described pathophysiology and the anticipated epidemiological burden in terms of high risk of vascular events and lower protection from antithrombotic prophylaxis, with particular reference to aspirin (ASA). Availability of high-throughput techniques is rapidly changing the way we address the problem, with a deeper insight into transcriptomics and posttranscriptional regulation of platelets as a consequence of the above-described metabolic abnormalities. This chapter will go through the body of evidence indicating a platelet hyperreactivity phenotype in diabetes, fostered by the variable contribution of a number of mechanisms driven by the metabolic abnormalities associated with T2DM and eventually affecting the platelet transcriptome and/or posttranscriptional regulation. These would include oxidative stress with isoprostane formation, inflammatory molecule production, endothelial dysfunction with circulating endothelial cells release, and cross-talk between cells with miRNA exchange through circulating extracellular vesicles.