Proton pump inhibitors (PPIs) are highly safe medicines, commonly used as first-line treatment for various digestive diseases. However, as the use of PPIs expands, hypersensitivity reactions (HSRs), including both immediate and delayed reactions, have become more prevalent. The most frequent HSR observed in patients treated with PPIs is anaphylaxis. Skin tests (prick and intradermal) followed by an oral challenge test are suggested for accurately diagnosing HSRs to PPIs, due to their high specificity. It is crucial to understand the patterns of cross-reactivity among different PPIs to establish a safe therapeutic option and evaluate alternative drugs within the same class. If the patient does not tolerate the available therapeutic options and no other equally effective chemically unrelated drugs are available, a desensitization protocol should be initiated to ensure continuous medical treatment.