The introduction of anti-tumor necrosis factor-a therapies has significantly expanded the armamentarium for patients with inflammatory bowel disease (IBD). Clinical experience has shown that not all patients respond to therapies in this class, which emphasizes the hypothesis that there are different pathways involved in the inflammatory cascade characteristic of the spectrum of IBD phenotypes. The broadening of therapeutics with different mechanisms of action and targets is important for patients with IBD. Based on evidence gathered in recent studies, the key to success with these therapies may lie in targeting the right patients based on knowledge of their underlying genetic defects and resultant immune reactivity. Determining the factors that can predict the progression from uncomplicated to complicated disease states may stratify patients into at-risk populations and have an impact on their ultimate therapeutic management.