This article focuses on lessons learned from clinical trials of antiplatelet therapies-in particular, that the degree of inhibition of ex vivo platelet aggregation does not necessarily directly translate into clinical efficacy. As an example, the case of the oral platelet glycoprotein IIb/IIIa inhibitors is presented, in which despite consistent evidence of substantial inhibition of platelet aggregation, this class of drugs provided no clinical benefit in Phase III trials and, in fact, was harmful. Several hypotheses for these unexpected findings have been proposed, but none has been confirmed. The connection between ex vivo inhibition of platelet aggregation and clinical benefit of platelet P2Y(12) antagonists is also not straightforward and is currently being tested in large clinical trials. A link between inflammatory status and clinical benefit from antiplatelet agents continues to emerge and highlights the fact that biomarkers beyond ex vivo platelet aggregation may predict the clinical benefit of antiplatelet agents that can reduce platelet activation (i.e., aspirin and thienopyridines). Results of past and ongoing trials hold valuable clues to determining the appropriate targets for maximizing antiplatelet efficacy, but the current lack of a proven ex vivo assay that correlates with clinical outcomes hampers clinical investigation, drug development programs, and clinical practice.