The European Medicines Agency (EMEA) recently issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors (PPIs) and recommended that the product information for all medicines containing clopidogrel be amended to discourage concomitant use of PPIs unless absolutely necessary. This follows a prior alert issued by the United States Food and Drug Administration (FDA) earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel. However, several experts have voiced their concern that the clopidogrel-PPI interaction has been given undue importance, given that all clinical studies suggesting this problem are observational. In this review, we critically analyze the available data and make practical suggestions for the clinician regarding appropriate use of PPIs in patients receiving clopidogrel. Based on currently available evidence, we suggest that the decision to prescribe a PPI to a patient on clopidogrel must be made on an individual patient basis balancing the gastrointestinal risk with the possible thrombotic risk and that PPIs should only be used for truly appropriate indications.