At present, iodinated contrast media (ICM) are mostly non-ionic, have low osmolality, and are safe. Even if adverse drug reactions (ADRs) occur, most are chemo-toxic symptoms and require only observation or H1 antihistamines. However, rare, unpredictable, and even life-threatening hypersensitivity can still occur. The aim of this review is to summarize the issues that all relevant staff need to know about and be able to respond to. The most significant risk factor for ICM hypersensitivity is a history of ICM hypersensitivity. For high-risk populations, we must cautiously weigh the advantages and disadvantages of premedication and be aware that breakthrough reactions may still occur. The best policy for patients with a history of severe ICM hypersensitivity is to avoid the same ICM. If ICM are inevitable, skin tests, in vitro tests, and drug provocation tests may help to find a feasible alternative that is safer. The severity of the hypersensitivity is correlated with the positivity rate of these tests, so there is no need for further investigations for patients with only mild reactions. We should also keep in mind that even excipients in ICM may induce hypersensitivity. Detailed, standardized documentation is essential for correct diagnosis and the prevention of future occurrence.