<p>Corticosteroids have long been a standard-of-care treatment for chronic immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, corticosteroids are associated with potentially serious adverse effects and may be ineffective in cases of resistant or refractory disease. Acthar^® Gel, a naturally sourced complex mixture of porcine pituitary peptides, is a noncorticosteroid alternative that is approved by the US Food and Drug Administration to treat a variety of IMIDs and autoimmune conditions. These include infantile spasms, systemic lupus erythematosus, exacerbations of multiple sclerosis and rheumatoid arthritis, and several ocular inflammatory disorders. Preclinical and clinical studies have shown that the immunomodulatory effects of Acthar Gel are distinct from those of corticosteroids and other adrenocorticotropic hormone (ACTH)–class therapeutics. For example, Acthar Gel stimulates both steroid-dependent and steroid-independent pathways that may mitigate inflammation. In this narrative review, we summarize the immunomodulatory effects of Acthar Gel, with a focus on its potential mechanisms in immune cells, such as B cells, T cells, and macrophages. These effects are thought to be mediated by binding and activation of transmembrane melanocortin receptors expressed on these immune cells. Receptor binding initiates an intracellular signal transduction cascade that ultimately regulates the expression of anti-inflammatory genes. Collectively, the experimental and clinical studies reviewed here suggest that Acthar Gel acts as an immunomodulator via melanocortin receptors and may be an effective anti-inflammatory therapeutic option for patients with IMIDs who are refractory or intolerant to corticosteroids.</p><p>Graphical Abstract available for this article.</p> Graphical Abstract <p></p>