Gadolinium-based contrast (GBC) exposure has recently been linked to the development of nephrogenic systemic fibrosis (NSF) in patients with underlying kidney disease and may in fact be the previously unrecognized trigger for the fibrosing process. As NSF is fairly rare in this patient population, a number of permissive factors are likely required for GBC exposure to initiate fibrosis. Advanced kidney disease is an absolute requirement whereas vascular injury and an inflammatory state, and a mix of co-factors including increased serum phosphate and calcium concentrations and iron overload further enhance risk. The combination of these events allows excess circulating gadolinium, which dissociates from its chelate to leak out of vessels and deposit in tissues. Free or bound tissue gadolinium, a rare earth metal of the lanthanoid series, promotes fibrosis via either direct binding to the collagen helix or, once the metal has been engulfed by macrophages, through the production of free oxygen radicals, cytokines, and other profibrotic factors that attract circulating fibrocytes to tissues. These fibrocytes then differentiate into fibroblast-like spindle cells that produce connective tissue matrix and other angiogenic and growth factors that further enhance tissue fibrosis. Direct gadolinium activation of transglutaminases on these tissue fibroblast-like cells may also promote fibrosis.