Nephrogenic systemic fibrosis is a rare fibrosing disorder associated with the use of gadolinium-based contrast agents in patients with renal dysfunction. However, only a small proportion of at-risk patients develops the disorder, and the exact determinants of disease are still not completely clear. Here, we present an update on emerging evidence for the role of gadolinium-based contrast agents, renal dysfunction, and background inflammation in disease expression, with a focus on current experimental models. Based on these findings, significant progress has been made in our understanding of the pathophysiology of this disorder over the last few years. This review provides a summary of these developments with discussion of the implications for clinical practice and directions for additional study.