Proton pump inhibitors (PPIs) have been recommended for reducing the risk of gastrointestinal bleeding associated with dual antiplatelet therapy (aspirin plus clopidogrel). However, studies have found decreased efficacy of clopidogrel when concurrently administered with a PPI. To determine the mechanism of and evidence for the potential interaction between clopidogrel and PPIs, along with the clinical implications of this drug interaction, we reviewed recently published reports of trials that examined the interaction. A MEDLINE database search (1966-September 2009) for English-language reports of clinical trials in human subjects was performed, supplemented by a manual search of reference lists. Four trials that examined surrogate outcomes and eight trials that examined clinical outcomes were included in this review. Two surrogate outcome studies showed that PPIs negatively affected clopidogrel response and increased platelet aggregation, whereas the other two did not find a significant difference between groups receiving PPIs and not receiving PPIs. Three of four published clinical outcomes studies and three of four unpublished clinical outcomes studies available as abstracts found a significant association between PPI use and rates of acute myocardial infarction, rehospitalization, death, or stroke. Most of the currently available data, primarily from observational studies, show that some PPIs may decrease clopidogrel's antiplatelet effectiveness, with increased cardiac adverse outcomes when clopidogrel is combined with PPIs. Although current data do not show causation of adverse outcomes with PPI use because the available data are conflicting, this topic is still controversial. Careful risk-benefit assessment is required before prescribing PPIs for individual patients taking dual antiplatelet therapy. More evidence from randomized controlled trials is needed to clarify this drug interaction dilemma.