Abstract: Aspirin is a widely used anti-platelet drug. However, patients continue to experience atherothromboembolic events despite aspirin therapy, which is known as “aspirin resistance(AR)”. Besides the traditional explanation from COX-1—dependent and COX-1—independent mechanism of aspirin resistance, the mechanism under physiological and pathological conditions related to aspirin resistance has been made further progress recently. This review provides a general overview regarding current knowledge about aspirin resistance from the perspective of the pharmacokinetic and pharmacodynamic mechanism under physiological and pathological conditions, respectively. These advances could guide future research toward aspirin resistance and provides potential strategies to improve aspirin efficacy.