Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is an established regimen to reduce the risk of ischemic event occurrence in patients with high-risk cardiovascular (CV) disease. Cigarette smoking is an important cardiovascular risk factor. However, several investigators have reported what may be termed a “new” “smoker's paradox”, whereby clopidogrel-treated nonsmokers appear to have either less or no CV-event reduction when compared to the substantial CV-event reduction in clopidogrel-treated smokers based on several large-scale trials. This “smoker's paradox” observed in multiple clinical outcome studies is also supported by emerging “real-world” data that also suggest clopidogrel nonsmokers do not fare as well as smokers treated with clopidogrel. In support of the new “smoker's paradox”, pharmacodynamic studies have also shown that smoking status influences clopidogrel responsiveness in healthy volunteers, acute coronary syndrome patients, and patients treated with percutaneous coronary intervention. Finally, there is a substantial, albeit not entirely consistent, body of pharmacodynamic and clinical outcome data supporting a reduced antiplatelet effect of clopidogrel in non-smokers as compared to smokers. The clinical relevance of this interaction has never been demonstrated in a prospective trial. The focus of this review is to critically evaluate the reported interaction between cigarette smoking status and thienopyridine efficacy.