With the introduction of biologic therapies for inflammatory bowel disease, significant questions have arisen regarding their best optimization. Although initial recommendations were to combine immunosuppressives with biologics to reduce immunogenicity, trials with 3 different anti-tumor necrosis factor agents (infliximab, adalimumab, and certolizumab) and a humanized monoclonal antibody that targets alpha-4 integrins (natalizumab) have failed to demonstrate the clinical superiority of combination therapy when high-dose induction and scheduled maintenance therapy was prescribed for up to 1 year. However, immunosuppressive agents should be considered with episodic biologic therapy to decrease immunogenicity and secondary loss of response. The issue of whether induction with biologics and maintenance therapy with immunosuppressives as monotherapy is as safe and effective as induction and maintenance with biologics alone still remains to be addressed. Further, with the use of concomitant immunosuppressives and biologics, evolving data raise concerns for an increase in adverse events, including opportunistic infections, neurological disorders, and cancer. Specific therapeutic decisions need to be individualized and the clinician must help the patient weigh quality-of-life issues with readiness to assume possible risks.