In the past few years, antagonists of tumour necrosis factor have resulted in unforetold therapeutic benefits in Crohn's disease, but the magnitude and duration of responses are variable. New agents are therefore needed. Their development has benefited from advances in the understanding of the pathophysiology of this disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. With increasing evidence of an implication of the innate immune system and the intestinal epithelium, the therapeutic paradigm is also shifting from mere immunosuppression to the reinforcement of the intestinal barrier. We review mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials. We discuss future directions, including new strategies with optimum endpoints.