Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.