Glycoprotein IIb-IIIa inhibitors provide the most benefit in patients with non-ST-elevation acute coronary syndromes and high-risk features and in those who undergo early invasive treatment. Current guidelines recommend glycoprotein IIb-IIIa inhibition in these patients but offer little guidance as to timing of initiation. Preliminary data suggest superior outcomes with upstream initiation (upon admission to a medical facility) compared with delayed initiation (in the catheterization laboratory, just before percutaneous coronary intervention). The availability of new antiplatelet and antithrombotic drugs renders even more complex the question of the best strategy.