Nonsteroidal anti-inflammatory drugs (NSAIDs) and Aspirin target cyclooxygenase (cox) enzymes and inhibit the synthesis of prostanoids. These drugs were originally developed to reduce the cardinal signs of inflammation, primarily pain. Prior to understanding their mechanism of action, investigations of Aspirin response in humans have revealed a protective effect on the cardiovascular system. Daily low-dose Aspirin is a well-established and prevailing treatment for the prevention of arterial thrombosis. Platelet inhibition by Aspirin results from the irreversible inhibition of cyclooxygenase-1 enzyme and prevention of thromboxane A2, a potent aggregatory agent, formation. In an effort to develop drugs with a safer profile for the stomach, a new form of cyclooxygenase was discovered. Subsequently and with the development of cloning strategies, cyclooxygenase-2 was cloned and characterized to have a profile of induction associated with the inflammatory reaction. This provided the rationale to target cox-2 enzyme and development of cox-2 selective drugs such as Vioxx and Celebrex. Coxibs were initially a successful treatment for arthritic patients also providing a reduction in gastric ulceration compared to traditional NSAIDs. Further investigations on the drug response to coxibs revealed a detrimental effect; the increase of myocardial infarctions, and the withdrawal of Vioxx from the market. The current theory to explain the harmful effect of coxib suggests the disruption of the platelet-endothelium interaction and selective inhibition of endothelium cox-2 activity depriving the cardiovascular system of vascular prostacyclin with anti-aggregatory activity. The balancing prostanoid theory to explain coxib cardiovascular complications was recently opposed. Recent investigations of Aspirin drug response have unraveled genetic variations in the cox-1 gene that are associated with the occurrence of Aspirin sensitivity or lack of protections against cardiovascular accidents. Screening for cox-1 gene variants will identify susceptible patients and reduce undesirable side-effects associated with Aspirin. Here we review recent findings in the cyclooxygenase-1 pathway and potential impact for the development of therapeutics that would segregate antithrombotic benefit from bleeding risk. Over 100 years following the initial use of Aspirin, cyclooxygenase inhibitors continue to be instrumental in our understanding of cardiovascular homeostasis and how the cyclooxygenase pathways are disrupted in disease.