Several distinct lines of investigation in the context of atherosclerosis dealing with low-grade inflammation, oxidative stress and platelet activation are now emerging, with CD40/CD40L system as the missing link. CD40 ligand is a transmembrane glycoprotein structurally related to tumour necrosis factor-α and more than 95% of the circulating CD40L derives from platelets. CD40L appears as a multiplayer of several cell types in the inflammatory network. The peculiarity of CD40L as an inflammatory mediator derived from platelets expands the functional repertoire of platelets from players of haemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation and cell-cell interactions. The multifunctional role of CD40L, as a simultaneous activator of all these systems, further blurs the intricate relationship between such events both in the physiological systems and the pathological derangement occurring in atherothrombosis.