Perioperative hypersensitivity reactions are rare, often life-threatening events, and subsequent investigations to identify the culprit are important to avoid re-exposure. All exposures in the perioperative setting may potentially be the cause of a hypersensitivity reaction, but drugs administered intravenously such as neuromuscular blocking agents (NMBA), induction agents and antibiotics have traditionally been reported to be implicated most commonly. It has recently become apparent that there are geographical differences in sensitization patterns related to variation in exposures, referral patterns and performance and interpretation of investigations. Differences in sensitization to NMBAs are partly explained by cross sensitization to pholcodine, an ingredient in cough-medicines available in some countries. While NMBAs are the most common causes of perioperative hypersensitivity in some countries, this may not necessarily be the case in all countries. New and hidden allergens have emerged as causes of perioperative hypersensitivity such as blue dyes, chlorhexidine and excipients. Detailed knowledge of the events at the time of reaction is necessary to identify potential culprits including rare and hidden allergens. Cooperation between allergists and anaesthetists, or other staff present perioperatively, is often needed to identify hidden or even undocumented exposures. The objectives of this review are to provide an overview of the history of investigation of perioperative hypersensitivity, to describe the differences in causes of perioperative hypersensitivity emerging over time and to increase awareness about the “hidden allergens” in the perioperative setting. Some practical advice on how to approach the patient testing negative on all initial investigations is also included.