Platelets have been found to play a critical role in the initiation of atherogenesis and atheroprogression. Plasma lipids have a major impact on platelet function. Plasma lipids and lipoproteins interact with the platelet plasma membrane and are actively internalized and alter the platelet lipidome. Hence, platelets are a “cargo” for oxidized lipoproteins. The induced change within the platelet lipidome enhances the prothrombotic and pro-inflammatory activity of platelets. These activated platelets interact with the intact endothelial monolayer and can initiate vascular inflammation at sites prone to develop atherosclerotic lesion and release platelet-derived inflammatory mediators, such as cytokines, chemokines, and DAMPs, that attract circulating blood cells to the inflammation. Phagocytosis of lipid-rich platelets by monocytes induces macrophage and foam cell generation, an early step of atherogenesis that precedes plaque formation. Inhibition of platelet activation, using a dual antiplatelet therapy (DAPT or DAT) in patients at high risk to develop atherosclerotic diseases, has the potential not only to avoid clinical complications such as myocardial infarction or ischemic stroke but also to prevent the development and progression of atherosclerotic plaques in nascendo.