Dual antiplatelet therapy with aspirin and clopidogrel is recommended in all patients who have had an acute coronary syndrome or who undergo percutaneous coronary intervention to prevent further ischemic events. Resistance or reduced responsiveness to aspirin and/or clopidogrel has been associated with adverse cardiovascular outcomes, including stent thrombosis. There have been significant advances in this field, which aim to overcome antiplatelet resistance, including the development of new antiplatelet agents. The rationale for dual antiplatelet therapy, the impact of suboptimal efficacy and the potential ways of overcoming resistance or variability in response to antiplatelet agents will be reviewed in this article.