Anaphylaxis is the most severe systemic hypersensitivity reaction, and it can be life-threatening or even fatal. It involves the activation of multiple immune and non immune pathways beyond IgE, thus exhibiting different phenotypes. New symptoms of hypersensitivity caused by chemotherapy drugs, monoclonal antibodies, and biological agents have been suggested to be recognized as anaphylaxis phenotypes. No biomarker has been described that allows an unequivocal diagnosis of anaphylaxis. Moreover, more biomarkers for specific endotypes are needed to stratify severity, to predict risk, and to optimaze tretament choice in the individual patient. Food, drugs and stinging insects represent the most commly identified triggers. Idiopathic anaphylaxis is a diagnosis of exclusion and it can hide a clonal mast cell disorder. Individual risk factors and co-factors may influence the severity of anaphylaxis or its onset, and they should be identified to implement the appropriate measures to prevent recurrence. Prompt recognition and treatment are critical in anaphylaxis, adrenaline being the first-line saving therapy. Individualized anaphylaxis action plan should include avoidance measures, prescription of an adrenaline autoinjector, education, optimal management of relevant comorbidities, venom specific immunotherapy, food oral immunotherapy, and drug desensitization, when appropriate. However, the quality of acute and long-term anaphylaxis management is variable influencing the poor outcomes experienced by many patients. Clinical practice guidelines have the potential to improve outcomes, but they often prove challenging to implement in routine clinical care.