Iodinated CM for intravascular use became available in the 1950s when creation of the tri-iodinated benzene ring led to the development of the agents now known as ionic, high-osmolality CM (HOCM). In the half century that has passed since then, non-ionic, monomer, low-osmolality CM (LOCM) have been developed, followed by non-ionic, dimer, iso-osmolar CM (IOCM). The HOCM have five- to eightfold the osmolality of plasma (>1500 mOsm/kg), LOCM, such as iopamidol, iohexol, and iomeprol, have two- to threefold the osmolarity (600–850 mOsm/kg), and IOCM, which are being used increasingly, such as iodixanol, have the same osmolality (290 mOsm/kg) as blood, plasma, and cerebrospinal fluid. One large study has shown that patients receiving HOCM have a 3.3-fold greater risk of developing CIN than those receiving LOCM.34 Possible explanations for the lower incidence of CIN after LOCM administration include reduced osmolality, as well as differences in iconicity and physiochemical properties.35 It has been suggested that if the lower risk of CIN associated with LOCM compared with HOCM is due to the lower osmolality of the former, then perhaps the even lower osmolality of IOCM may further decrease the risk of CIN. Given the conflicting results of many studies that have compared the CIN risk of IOCM and various LOCM,11–14,16,17,36,37 we believe that, at present, a clear benefit of IOCM has yet to be demonstrated. Currently, HOCM tends to be used rarely.