Clopidogrel therapy, the most widely used P2Y ₁₂ receptor blocker, is associated with widely variable pharmacodynamic response where approximately nearly 40% of clopidogrel-treated patients may have high platelet reactivity to adenosine diphosphate stimulus (HPR). HPR strongly correlates with worse clinical outcomes in high-risk clopidogrel-treated patients who have undergone PCI. Most of the studies linking HPR to thrombotic event occurrence have employed a peri-procedural platelet reactivity measurement. Treatment with more potent P2Y ₁₂ receptor blockers, such as prasugrel and ticagrelor, is associated with faster and greater platelet inhibition than clopidogrel therapy and is a credible strategy to overcome HPR on clopidogrel. Selective treatment of patients with HPR during clopidogrel therapy with potent P2Y12 receptor blockers based on platelet function testing may reduce post-stenting ischemic events. On the other hand, there is emerging evidence to suggest that platelet function guided therapy may decrease bleeding, by averting overuse of potent P2Y ₁₂ inhibitors. The therapeutic window concept for the P2Y ₁₂ receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome. In the absence of evidence from a definitive clinical trial, at this time, we must rely on the guidelines and the existing observational data while fully keeping in mind the pivotal role of platelet activation in ischemic events and of excess platelet inhibition in bleeding.