In clinical practice, significant discrepancies occur between disease activity and severity, and the patient's symptom experience and behavior. Discrepancies cannot be explained by biologic or morphologic findings, and usually are considered to be related to psychosocial factors. Recent advances in the scientific understanding of the relationship between environmental stress and the neural, endocrine, and immune systems, combined with new methodologies in clinical research, provide a challenging opportunity for clinicians and researchers to establish a more comprehensive understanding of Crohn's disease. This article reviews the important relationship of psychosocial factors, pathogenesis, clinical expression, response to treatment, and outcome of Crohn's disease, and presents a comprehensive model of illness, disease, and ways to integrate psychosocial factors with diagnosis and patient care.