Anaphylaxis is an acute life-threatening systemic allergic reaction that can have a wide range of clinical manifestations, including urticaria, respiratory distress, nausea, vomiting, diarrhea, and/or hypotension [1]. In children, the most common causes of anaphylaxis are foods, including egg, cow’s milk, wheat, peanut, tree nut, fish, shellfish, and soy, yet it is possible that the induction and effector mechanism induced by each of these food allergens differs. While some food allergies can persist into adulthood, the most common triggers of anaphylaxis in adults are instead medications and venom [2]. Medications accounted for more than half of severe fatal anaphylaxis in the United States over a 12-year period [3]. While the culprit drug was not specified in the vast majority of these cases, antibiotics, radiocontrast media, neuromuscular blocker agents (NMBAs), and antineoplastic agents were implicated at the highest frequencies [3]. In regard to venom-induced anaphylaxis, Hymenoptera (bee and wasp) stings are the most prominent causes in North America and Europe, however, reactions to the venoms of snakes, other invertebrates, and cold-blooded vertebrates have also been described [4]. Mast cells (MCs) are essential mediators of anaphylaxis, likely for all of these classes of triggers, although other cell types can contribute. Classically, cross-linked IgE bound to its high-affinity receptor induces MC mediator release. However, toll-like, complement, or Mas-related G-protein-coupled (MRG) receptors and even non-IgE antibodies also activate mouse and human MCs [5]. This review will highlight basic science developments over the past five years regarding our evolving understanding of anaphylaxis to food, medications, and venom.