Purpose of Review <p>Systemic autoinflammatory disorders (SAIDs) are a group of diseases that are characterized by recurrent or persistent unprovoked attacks of inflammation resulting from innate immunity dysregulation and leading to significant sequelae in many cases. The concept of autoinflammatory disorders has been widely studied in the last 28 years since the genetic mutation responsible for familial Mediterranean fever (FMF) was discovered. These disorders are mainly hereditary autoinflammatory diseases with key immunological pathways affected and particularly involving inflammasomes, nuclear factor-κB dysregulation and interferon upregulation. This article serves as an overview of pediatric systemic autoinflammatory disorders, their presentation, workup, complications, and therapeutic management.</p> Recent Findings <p>Advances in genetic analysis have allowed for the rapid identification of mutations responsible for many autoinflammatory disorders. Advances in biomolecular techniques, which have allowed for identifying key players such as inflammasomes, have led to treatment options that have significantly improved morbidity and mortality in affected patients.</p> Summary <p>This review provides an overview of the proposed pathogenesis, presenting features, potential complications and suggested therapies of systemic autoinflammatory disorders. Providers should have a high clinical suspicion for autoinflammatory disorders in children who present with fever, a heightened inflammatory response and negative evaluation for an infectious, malignant, and autoimmune etiology. Understanding and identifying these disorders in a timely manner and implementing prompt treatment allow for the best possible outcome for these patients.</p>