Cardiovascular disease is the leading cause of death in western societies, with further increasing incidence. Therefore both, primary and secondary prevention play a pivotal role. Medicamentous prevention schemes include the antithrombotic drugs acetylsalicylic acid (ASS) and clopidogrel. A number of studies tested the efficacy and safety of ASS for primary prevention. A meta-analysis of these primary prevention trials could demonstrate a decrease of cardiovascular events only for patients being at high cardiovascular risk. However, since ASS does not influence the mortality but is significantly increasing the risk for bleeding, careful risk stratification is indispensable prior to preventive chronic administration of the drug. Therapy with ASS in the secondary prevention is commonly accepted and clearly evidence-based given that a meta-analysis of 145 trials could demonstrate a significant decrease in mortality. A daily dose of 100 mg has been shown to achieve sufficient antithrombotic effects with an acceptable rate of side effects. Clopidogrel is currently not used for primary prevention, since evidence is lacking and the costs are high. For secondary prevention after acute coronary syndromes, a decrease of cardiovascular events could be demonstrated for clopidogrel. This benefit was especially pronounced after percutaneous coronary interventions. However, clopidogrel could not decrease the mortality. Therefore, long-term treatment with clopidogrel in the secondary prevention should be based on a critical appraisal of risk and benefit on the one hand and socioeconomic aspects on the other hand.