In patients with well-preserved renal function, the choice of contrast agent appears to have little impact on the development of contrast-induced nephropathy (CIN). However, in patients with underlying renal insufficiency and diabetes mellitus, it has been shown that the use of low-osmolar media is associated with a lower incidence of CIN compared with high-osmolar agents. Previously, it was unknown whether further benefit would be derived from the use of iso-osmolar contrast media. Recent studies, including Nephrotoxicity in High-Risk Patients Study of Iso-osmolar and Low-Osmolar Nonionic Contrast Media (NEPHRIC), have shown a reduction in the incidence of CIN with the iso-osmolar contrast agent iodixanol compared with low-osmolar agents in patients with renal insufficiency and diabetes. The peak rise in serum creatinine was significantly reduced with iodixanol (0.13 mg/dL vs 0.55 mg/dL, P < .001). The incidence of CIN, defined as a peak rise > 0.5 mg/dL, was decreased from 26% to 3%, P < .0002 when iodixanol was used. An ongoing, multicenter, prospective, double-blind, randomized study (Visipaque Angiography/Interventions with Laboratory Outcomes for Renal Insufficiency [VALOR]) is evaluating the potential benefit of iodixanol in reducing CIN in patients with preexisting renal impairment. Accumulating evidence suggests that the use of iso-osmolar contrast agents in conjunction with other proven measures, especially adequate intravenous hydration and contrast dosage limitation, can reduce the morbidity and mortality associated with CIN. These measures have the potential for a significant reduction in health care costs.