Experimental studies suggest that the pathogenesis of contrast media nephrotopathy is due to a combination of renal ischemia and direct tubular epithelial cell toxicity. Clinical studies to date have demonstrated a reduction in clinical contrast nephropathy with the introduction of low-osmolar and, more recently, iso-osmolar contrast media. Numerous experimental studies have examined the role of osmolality per se in the pathogenesis of contrast nephropathy, with conflicting results. Whether iso-osmolar contrast media are the least nephrotoxic iodinated contrast media needs to be determined with large prospective randomized clinical trials.