Anti–tumor necrosis factor (TNF) therapy has revolutionized the treatment of inflammatory bowel disease (IBD). However, up to 30% of patients with IBD show no clinical benefit and are defined as having a primary nonresponse. Primary nonresponse to a biologic can be attributed to either pharmacokinetic or pharmacodynamic issues, such as those involved in secondary loss of response. Pharmacokinetic issues are linked to undetectable or subtherapeutic drug concentrations because of either an accelerated non–immune-mediated clearance or immunogenicity and the development of antidrug antibodies, whereas pharmacodynamic issues are likely related to “non-TNF driven” disease. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, has been proven effective for optimizing anti-TNF therapy in IBD. Nevertheless, most of the data for TDM relate to patients losing response during maintenance therapy, whereas much less is known about the therapeutic drug window and use of TDM during anti-TNF induction therapy. Recent exposure–response relationship studies, though, demonstrate that high serum anti-TNF drug concentrations during and early after induction therapy are associated with favorable therapeutic outcomes in IBD. This suggests that early optimization of anti-TNF therapy may prevent some of the primary nonresponse related to pharmacokinetic issues (low drug concentrations) and lead to better short- and long-term outcomes. This review will focus on the role of TDM during the induction phase of anti-TNF therapy.