Proton pump inhibitors (PPIs) are recommended in patients with prior upper gastrointestinal bleeding and considered appropriate in patients with multiple other risk factors who require dual antiplatelet treatment (DAPT). During the past few years, however, concerns have been raised about the potential for PPIs, especially omeprazole, to decrease the efficacy of clopidogrel, and both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued warnings regarding the concomitant use of these medications. A review of the literature revealed that the pharmacodynamic studies support an interaction, whereas the clinical evidence, which is mainly based on non-randomized, observational studies and secondary analyses of randomized trials, is conflicting. We conclude that PPIs should be prescribed together with DAPT for patients in whom they are recommended according to the guidelines and for patients with other indications. With respect to omeprazole, current evidence does not allow clear recommendations to be provided.