Aspirin remains the most widely used drug in patients with cardiovascular disease to prevent acute ischemic events. Its daily administration reduces the risk of stroke, myocardial infarction and death by approximately 25%. However, inhibition of platelet aggregation by aspirin is variable, the cause of this phenomenon being most likely multifactorial. Several intrinsic mechanisms may contribute to modulating platelet response to aspirin, in addition to various extrinsic factors not related to platelet activation pathways. Moreover, the currently available platelet function assays target different pathways of platelet activation, and may also contribute to the variability of the measured platelet response to aspirin. Therefore, judicious use of these assays, through better understanding of their value and limitations in assessing platelet function, as well as a better understanding of the various factors influencing platelet aggregation, should lead the way towards better individualized antiplatelet therapy, offering both adequate inhibition of platelet aggregation and reduced risk of bleeding.