Identifying the culprit medication in cases of perioperative anaphylaxis can be extremely challenging. A detailed and accurate history, coupled with the appropriate testing, plays a key role in discovering the etiology of perioperative anaphylaxis. We present the case of a 48-year-old woman with a cranial meningioma who was scheduled for surgery. Chlorhexidine, midazolam, lidocaine, propofol, fentanyl, rocuronium, and furosemide were administered during the perioperative period. She developed hypotension, urticaria, bronchospasm, and other symptoms of anaphylaxis soon after general anesthesia. The serum tryptase level obtained during anaphylaxis was 119 ng/mL (normal, <11.4 ng/mL). Epinephrine was administered, and the surgery was canceled, with no cause identified. For the next surgical attempt, she was pretreated with diphenhydramine and ranitidine, and the neuromuscular blocker was withheld. Again, she developed hypotension consistent with anaphylaxis, and epinephrine was administered. She was referred for consultation. A detailed and accurate history was obtained. The baseline serum tryptase level was 6.4 ng/ mL. Skin-prick puncture tests were completed, and a diagnosis was made. The surgical team was instructed to avoid the culprit medication, and the cranial surgery was successful. Although difficult, cases of perioperative anaphylaxis can be solved with a detailed history, keen detective work, and appropriate testing.