Recent randomized clinical trials with intravenous glycoprotein IIb/IIIa inhibition have provided unanticipated results, thereby questioning their role as empirical medical management for acute coronary syndromes. The lack of benefit with abciximab observed in Global Utilization of Strategies to Open Occluded Coronary Arteries IV is somewhat inconsistent with the benefits seen with this agent in coronary intervention, and the benefits of an early invasive approach incorporating tirofiban seen within Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy Thrombolysis in Myocardial Infraction 18. Additionally, a direct 'head-to-head' comparative study of abciximab and tirofiban within the setting of percutaneous coronary intervention demonstrates clinically relevant superiority with abciximab with respect to 30-day outcomes. in the setting of coronary instability and mechanical plaque disruption is more complex than initially perceived. Hence, although an abundance of evidence details the efficacy of these agents, their optimal clinical application remains somewhat challenging in light of these recent data. However, within the context of previous trial experience, the current evidence highlights several key aspects of glycoprotein IIb/IIIa inhibitor therapy that may be associated with improved patient outcomes. In particular, these trials indicate: (i) the importance of selecting high-risk patients in whom substantial clinical benefit is evident, (ii) the incorporation of these agents into an early invasive strategy, thereby matching the timing of vascular injury with maximal platelet inhibition and (iii) optimal dosing to achieve the high levels of platelet inhibition that appear to be required for efficacy with these agents.