Patients who respond to infliximab enjoy many benefits, including improvement in clinical symptoms, less disability, and a better quality of life. Unfortunately, many patients are unresponsive to infliximab therapy. They may be completely refractory to infliximab therapy (ie, primary nonresponders), they may have shown an initial response to therapy that subsequently diminished, or they may be hypersensitive to the drug. For these patients, second-generation tumor necrosis factor (TNF) inhibitors will soon be available; adalimumab and certolizumab pegol are the two agents most likely to gain Food and Drug Administration approval for the treatment of Crohn's disease. This article looks at recent studies using these newer TNF inhibitors in patients in whom infliximab treatment has failed as well as in those who have never received infliximab.