The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunological adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, like systemic lupus erythematosus. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage’s role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment.Copyright © 2023. Published by Elsevier Inc.