Aspirin is one of the most widely used antithrombotic agents worldwide. Nevertheless, the concept of aspirin resistance has generated sustained controversy for more than 2 decades. Initially introduced in the mid-1990s, the term was inconsistently applied to describe either recurrent ischemic events, despite aspirin therapy, or inadequate platelet inhibition, as measured using various laboratory assays. Reported prevalence estimates consequently varied widely, reflecting profound methodological and semantic heterogeneity rather than a uniform biological concept. This historical review retraced the evolution of knowledge about aspirin pharmacodynamics, from the earliest studies on bleeding time and platelet aggregation to the identification of platelet cyclo-oxygenase-1 as aspirin's molecular target and the recognition of serum thromboxane B₂ as a specific biomarker of target inhibition. We examined how reliance on integrative platelet-function tests fostered the concept of apparent resistance, later recognized, in many cases, as pseudo-resistance related to assay choice or pharmacokinetic factors. We then reviewed the clinical, genetic and disease-related determinants of variability in aspirin response, highlighting conditions characterized by accelerated platelet production and turnover, such as essential thrombocythaemia, as a notable exception in which target-guided dosing has influenced practice. Finally, we summarized the outcome studies and guideline statements that uniformly discourage routine testing and aspirin dose escalation. Taken together, the historical evidence supports abandoning the term aspirin resistance in favor of recognizing the variability in platelet reactivity found among patients treated with aspirin.