The chronic course of inflammatory bowel disease (IBD) leads to recurrent episodes of active clinical symptoms, as well as long term complications, including hospitalizations, surgeries, and a decreased quality of life. Biologic agents have been shown to be effective for the induction and maintenance of remission in patients with moderate to severe IBD, and may alter the natural history of disease. Loss of response to biologic therapy is a common problem in clinical practice, the reasons for which are likely multifactorial; antibody development, alterations in drug clearance, and possibly a change to a non-TNF-driven inflammatory mechanism. Several studies have evaluated interventions that may lead to an increased rate of response and an increase in the durability. In this review, we evaluate ways to maximize anti-TNF treatment by administering scheduled therapy, using concomitant immunomodulator therapy, escalating dosage, and switching between biologic agents and classes. Finally, the role of antibody to infliximab (ATI) and infliximab serum trough levels are discussed in the context of optimizing biologic therapy for inflammatory bowel disease.