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Purpose of Review: Anaphylaxis is a severe, and potentially life-threatening hypersensitivity reaction whose diagnosis is based on clinical signs and symptoms and their prompt recognition. The presence of mimics and unusual presentations necessitate a careful evaluation and expertise in the field, due to potential diagnostic errors and hence a delay in the treatment.The aim of this review is to analyze and make an overview of the potential differential diagnosis of anaphylaxis, focusing on the clinical challenges of recognizing these conditions effectively among similar others., Recent Findings: The presence of mimics and unusual presentations of anaphylaxis necessitate a careful evaluation, emphasizing the importance of a comprehensive diagnostic approach.Tryptase is well known marker of mast cells activation, and a useful tool assisting the diagnosis of anaphylaxis, helping to differentiate it from atypical mimickers., Summary: The differential diagnosis of anaphylaxis comprises a very wide setting, and a systematic approach assessing different categories of cardiovascular, skin, respiratory airway, neuropsychiatric, and hematologic systems, can facilitate recognition of the correct diagnosis of this complex and life-threatening condition., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)