INTRODUCTION: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the 'wide variability' and the phenomenon of 'antiplatelet resistance'. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a 'therapeutic window' of P2Y12 receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed. AREAS COVERED: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y12 receptor blocker therapy was collected from a selective literature search. EXPERT OPINION: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y12 receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.