The survival of aspirin in the cardiovascular armamentarium and its persistent pre-eminence in treatment guidelines, 125 years after marketing, is due to several factors: (i) a unique mechanism of action that, together with simple pharmacokinetics, makes it ideally suited to act as an antiplatelet agent; (ii) the discovery and utilization of a mechanism-based biomarker for dose-finding studies in health and disease; (iii) the unusual clinical development of low-dose aspirin driven by the medical/scientific community, and characterized by a very large number of investigator-initiated randomized clinical trials spanning the whole cardiovascular risk continuum. Aspirin has also provided a formidable investigative tool to explore the role of abnormal platelet activation in other areas of human pathophysiology, such as colorectal carcinogenesis. These recent findings open future directions for a potential third life of aspirin as a chemopreventive agent.