Immune-mediated inflammatory disorders (I.M.I.D.s) are a group of diseases that involve an immune response that is inappropriate or excessive, and is caused, signified, or accompanied by dysregulation of the body's normal cytokine milieu. I.M.I.D.s cause acute or chronic inflammatory injury, sometimes severe, in any organ system. Despite strong evidence linking the pathophysiologies and treatments of the diseases that constitute the I.M.I.D. group, providers, payers, employers, and benefits consultants have been slow to adopt the I.M.I.D. concept. As a result, these stakeholders risk underestimating the significant clinical and economic burdens of the I.M.I.D. class. In this review we examine those burdens, specifically analyzing I.M.I.D. prevalence and cost data for a group of large employers. We also describe the scientific rationale for the I.M.I.D. paradigm, examine the cytokine dysregulation that many I.M.I.D.s share, and focus in detail on the pathophysiology of 3 I.M.I.D.s with high morbidity: rheumatoid arthritis, Crohn's disease, and type 1 diabetes mellitus. The review concludes with an evaluation of approved anticytokine I.M.I.D. therapies and those in development.