The zebrafish has proved to be an informative model of vertebrate development and, more recently, an emerging model of human disease. The realization of the full potential of the zebrafish as a disease model lies in two interdependent areas. The first is an appreciation that the often overlooked strength of this species lies in allowing the design of experiments that address the interplay of genetics and the environment in a manipulable manner. The second is in the application and further development of gene targeting approaches. These twin features will be addressed in this review in the context of modeling inflammatory bowel disease.