Platelets have a pleiotropic range of biological roles that extend beyond hemostasis. The breaching of tissue homeostasis leads to platelet activation, a common event in various causes of tissue injury, traumatic, infectious, ischemic, autoimmune… Platelet activation, apart from its essential role in bleeding arrest, is the source of a flow of information that fuels the inflammatory reaction. Platelets represent host defense machines against infection, via the clearing of pathogens and the expression of membrane-bound and soluble signals that regulate the innate and adaptative arms of the immune response. Pathways activated in inflammation, coagulation, vascular/tissue repair and host defense are connected via soluble and cell-mediated signals, providing a coherent biological response aiming at arresting bleeding, curing infection and reestablishing tissue homeostasis. CD154 interfaces with many of these pathways (see Figures 2 and 3); activated platelets express a membrane-bound form of CD154 and release a soluble form (sCD154). Platelet derived microparticles (PMPs) recapitulate several of activated platelet functions (see text for details). Only some relevant molecules have been depicted. Small circles symbolize secreted molecules, large circles membrane-associated molecules. Abbreviations: CAMs, cell adhesion molecules; Fg, fibrinogen; Fn, fibronectin; ECM, extracellular matrix; NET ind., neutrophil extracellular traps induction; PAF, platelet activating factor; ROS, reactive oxygen species; Vn, vitronectin; vWF, von Willebrand factor.