Twenty-five years have passed since Vane and colleagues proposed a prostacyclin and thromboxane balance as critical to cardiovascular homeostasis. Prostacyclin prevents platelet aggregation and promotes vasodilatation, opposing the effects of thromboxane. Possible compensation by redundant functions, such as nitric oxide, long prevented appreciation of this balance. Effective use of low-dose aspirin in the secondary prevention of atherothrombosis suggested a clinical importance for the balance. However, it was not until the cyclooxygenase-2 inhibitor rofecoxib was withdrawn because of increased cardiovascular events that this critical balance was confirmed in humans. Moreover, clinical observations are supported by elegant animal receptor knockout experiments and subsequent human genetic variant studies. Combined, these findings provide valuable insight into the roles of these prostanoids in the development of atherothrombosis, emphasizing the need to reevaluate the use of selective prostacyclin- and thromboxane-based therapies in cardiovascular disease.