Circulating blood platelets play a central role in the maintenance of hemostasis. They adhere to subendothelial extracellular matrix proteins that become exposed upon vessel wall damage, which is followed by platelet activation, further platelet recruitment, platelet aggregation and formation of an occlusive, or non-occlusive, platelet thrombus. Platelets host a surprisingly diverse transcriptome, which is comprised of ˜9500 messenger RNAs (mRNAs) and different classes of non-coding RNAs, including microRNAs, as well as a significant repertoire of proteins that contribute to their primary (adhesion, aggregation, granule secretion) and alternative (RNA transfer, mRNA translation, immune regulation) functions. Platelets have the propensity to release microparticles (MPs; 0.1-1 μm in diameter) upon activation, which may mediate inflammatory responses and contribute to exacerbate inflammatory diseases and conditions. Carrying components of the platelets' cytoplasm, platelet MPs may exert their effects on recipient cells by transferring their content in platelet-derived bioactive lipid mediators, cytokines, mRNAs and microRNAs. Platelet MP-associated microRNAs may thus function also outside of platelets and play an important role in intercellular signaling and gene expression programming across the entire circulatory system. The role and importance of platelet MP-associated microRNAs in various aspects of biology and pathophysiology are increasingly recognized, and now provide the scientific basis and rationale to support further translational research and clinical studies. The clinical significance, pathophysiological role as well as the diagnostic and therapeutic potential of platelet MP-associated microRNAs in cardiovascular diseases, platelet transfusion and cancer will be discussed.