Cardiovascular disease remains the main cause of death worldwide. For this reason, strategies for the primary prevention of atherosclerosis and atherosclerosis-related pathologies like stroke or myocardial infarction are needed. Platelets are key players of atherosclerosis-related vascular thrombotic pathologies and their role as targets in secondary prevention of atherosclerosis-related complications is uncontested. However, platelets also play an important role in the initiation and progression of atherosclerosis. Currently, though, there is no generally valid recommendation for the use of antiplatelet therapy in primary prevention of cardiovascular disease. Recent clinical studies have shown that the benefit from antiplatelet therapy in primary prevention is counteracted by the entailed bleeding risk. This review addresses the important role platelets play in initiating and sustaining vascular inflammation, which drives atherosclerosis. Specifically, platelet-lipid interactions as well as platelet-endothelium interactions in the context of atherosclerosis are illustrated. We also depict how platelets help recruit immune cells like monocytes, neutrophils or dendritic cells to the subendothelial space. Finally, we portray the role of complement and platelets in atherosclerosis. Platelets appear to act as mediators of tissue homeostasis and may also modulate the microenvironment of the atherosclerotic plaque. Overall, this review addresses the role of platelets in atherosclerosis with particular focus on potential targets for pharmacological interventions into platelet functions distinct from aggregation. By eliminating the bleeding risk of antiplatelet therapy, platelets are likely to regain a role in primary prevention of cardiovascular disease.