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Role for mast cell CRF1 in potentiating mast cell degranulation in response to immunological and psychological stressors. Life stress is a major risk factor in the onset and exacerbation of mast cell–associated diseases, including allergy/anaphylaxis, asthma, and irritable bowel syndrome. Although it is known that mast cells are highly activated upon stressful events, the mechanisms by which stress modulates mast cell function and disease pathophysiology remains poorly understood. Here, we investigated the role of corticotropin‐releasing factor receptor subtype 1 (CRF1) in mast cell degranulation and associated disease pathophysiology. In a mast cell–dependent model of IgE‐mediated passive systemic anaphylaxis (PSA), prophylactic administration of the CRF1‐antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell–deficient KitW‐sh/W‐shmice engrafted with CRF1−/−bone marrow–derived mast cells (BMMCs) exhibited attenuated PSA‐induced serum histamine, hypothermia, and clinical scores compared with wild‐type BMMC‐engrafted KitW‐sh/W‐shmice. KitW‐sh/W‐shmice engrafted with CRF1−/−BMMCs also exhibited suppressed in vivo mast cell degranulation and intestinal permeability in response to acute restraint stress. Genetic and pharmacologic experiments with murine BMMCs, rat RBL‐2H3, and human LAD2 mast cells demonstrated that although CRF1activation did not directly induce MC degranulation, CRF1signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca2+from intracellular stores. Taken together, our results revealed a prominent role for CRF1signaling in mast cells as a positive modulator of stimuli‐induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.