Proton-pump inhibitor failure has become a common clinical dilemma in gastrointestinal clinics and has been increasingly encountered at the primary care level as well. Underlying mechanisms are diverse and may overlap. Most patients who have proton-pump inhibitor failure are likely to originate from the non-erosive reflux disease phenotype. Currently, available diagnostic modalities provide limited clues to the exact underlying cause. Treatment relies primarily on escalating dosing of proton-pump inhibitors. However, new insights into the pathophysiology of proton-pump inhibitor failure are likely to provide alternative therapeutic options.