The efficacy of antiplatelet therapy for the secondary prevention of cardiovascular disease after an ischemic event is well established. However, the role for antiplatelet therapy for the primary prevention of cardiovascular disease is more complex because of the interplay of efficacy vs safety in individuals without established cardiovascular disease who have a relatively low, but linear trajectory of cardiovascular risk. Several large randomized trials have investigated the efficacy and safety of antiplatelet therapy (primarily aspirin) for patients without established cardiovascular disease. The pharmacological profile of the most commonly used primary prevention antiplatelet agent, aspirin, has been delineated by randomized clinical trials and showcased in practice guidelines for reducing cardiovascular risk. For this indication, aspirin has been consistently shown to reduce the risk of non-fatal myocardial infarction with little impact on cardiovascular death, but with a consistent increased risk of bleeding. These divergent results have contributed to differences in the recommendations from international practice guidelines and highlight controversy at the forefront of considerations for anti-platelet therapy for primary prevention. However, further studies in specific sub-groups of patients without established cardiovascular disease such as those with Diabetes Mellitus, chronic kidney disease, or the elderly may clarify which patient groups will benefit the most from aspirin treatment for the primary prevention of a cardiovascular event.