Biologic therapies such as infliximab and adalimumab have become mainstays of treatment for inflammatory bowel disease. Early studies suggested that combination therapy (CT) with infliximab and an immunomodulator drug such as azathioprine may help optimize biologic pharmacokinetics, minimize immunogenicity, and improve outcomes. The landmark SONIC trial in Crohn's disease and the UC SUCCESS trial in ulcerative colitis demonstrated CT with infliximab and azathioprine to be superior to monotherapy with either agent alone at inducing clinical remission in treatment naïve patients with moderate to severe disease. However, many unanswered questions linger. The role of CT in non-naive patients as well as the optimal duration of CT remains unknown. The effectiveness of CT with alternate biologics and/or alternate immunomodulators is not as clear, and it is unknown whether SONIC's conclusions can be extrapolated beyond infliximab and azathioprine. Also looming are the risks of CT including opportunistic infection and malignancy; specifically, lymphoma. This review lays out the evidence as it pertains to the risks and benefits of CT as well as the areas that require further research. With this information in hand, the practitioner may develop a treatment strategy that best suits each individual patient.