The therapy of Crohn's disease is constantly evolving. It is widely recognized that clinical assessment does not stage disease activity accurately and that endoscopic healing is associated with improved long-term outcomes. Disease management is therefore transitioning to a new paradigm that includes direct assessment of disease severity (endoscopically in most patients), followed by assessment of mucosal healing. New approaches have helped optimize the use of the thiopurines, methotrexate and anti-TNF agents. Novel agents with different mechanisms of action are expanding our therapeutic armamentarium. The major challenge of the future will be to identify patient subgroups best suited to particular therapeutic approaches. In the meantime, studies of comparative effectiveness will be crucial in positioning therapies relative to each other.