The introduction of monoclonal antibody therapy directed against tumor necrosis factor-α revolutionized the modern management of patients with IBD. In spite of this, a proportion of patients do not initially respond to this therapy or, of those that do, some lose response with time. The mechanisms for loss of response include immunogenicity leading to increased drug clearance. In this regard, a growing body of evidence has demonstrated a relationship between circulating drug levels, anti-drug antibodies, and clinical outcomes. This article addresses these issues in the context of therapeutic drug monitoring and aims to give the treating clinician a platform upon which to make clinical decisions to guide management of loss of response. Inflamm Bowel Dis Monit 2014;14(2):44–53.