Clopidogrel is one of the most commonly prescribed medications worldwide. Recent advisories from the US Food and Drug Administration have drawn attention to the possibility of personalized decision-making for people who are candidates for clopidogrel. As is the case with antihypertensives, statins, and warfarin, common genetic sequence variants can influence clopidogrel metabolism and its effect on platelet activity. These genetic variants have, in multiple studies, been associated with adverse clinical outcomes. Concurrent medication use also influences how the body handles clopidogrel. Proton pump inhibitors, widely prescribed in conjunction with clopidogrel, may blunt its effectiveness. We address implications for bedside decision-making in light of accumulated data and current Food and Drug Administration advisories and conclude that genetic testing for CYP2C19 genotype and limitation of proton pump inhibitor interactions do not yet appear to offer an opportunity to optimize treatment given the current state of knowledge.