Nephrogenic systemic fibrosis (NSF) is a systemic illness, which only affects patients with kidney failure. NSF risk increases with progressively lower levels of kidney function. It is characterized by red skin areas or plaques that develop over several weeks to painful thickened skin with a "woody" texture, resembling "peau d'orange." It may ultimately cause flexion contractures of joints. Skin biopsy reveals thickened collagen bundles, mucin deposition, proliferation of fibroblasts and elastic fibers, without inflammation. Originally described as nephrogenic fibrosing dermopathy (NFD), because of its primarily cutaneous manifestation, it was renamed NSF because of the involvement of various organs like the lungs, myocardium, or striated muscles. The pathogenesis of the disease is not known yet, but recently we suggested a strong association between development of NSF and exposure to gadolinium-based contrast (GBC) agents, thereafter confirmed by other authors. As a consequence of our recent observations, medical authorities imposed restrictions that exclude patients with advanced levels of renal insufficiency from potentially important magnetic resonance imaging studies with gadolinium. Unfortunately, the only alternatives in many situations (examination of brain, lungs, vasculature) are imaging modalities using iodinated radiocontrast agents. Thus, clinicians are faced with weighing the potential risk of NSF from GBC exposure against the risk of acute kidney injury-associated with radiocontrast media. In this dilemma, clinicians must identify patients at high-risk to develop NSF. Known risk factors critical for the development of NSF after exposure to GBC agents (certain chelates and higher doses) are end-stage renal disease requiring dialysis, especially those with little or no residual renal function, and advanced kidney disease not on dialysis. Other potential risk factors include metabolic acidosis, iron overload/intravenous iron, divalent ion disturbances, endothelial/vascular injury, and high erythropoietin doses. Further studies are required.