One of the most important blood tests in the field of allergy, mast cell tryptase has numerous diagnostic uses, particularly for anaphylactic reactions and for the diagnosis of mastocytosis. However, there are numerous other non-anaphylactic conditions where clinicians may see elevated serum tryptase (hypertryptasemia) and the practicing clinician ought to be aware of these important differential diagnoses. Such conditions include systemic mastocytosis, hematological malignancies, and chronic kidney disease. This article provides a comprehensive, updated summary on the variety of non-anaphylactic conditions where hypertryptasemia may be seen.