Crohn's disease is a relapsing systemic inflammatory disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations and associated immune disorders. Genome wide association studies identified susceptibility loci that—triggered by environmental factors—result in a disturbed innate (ie, disturbed intestinal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response and autophagy, impaired recognition of microbes by pattern recognition receptors, such as nucleotide binding domain and Toll like receptors on dendritic cells and macrophages) and adaptive (ie, imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota. We discuss the epidemiology, immunobiology, amd natural history of Crohn's disease; describe new treatment goals and risk stratification of patients; and provide an evidence based rational approach to diagnosis (ie, work-up algorithm, new imaging methods [ie, enhanced endoscopy, ultrasound, MRI and CT] and biomarkers), management, evolving therapeutic targets (ie, integrins, chemokine receptors, cell-based and stem-cell-based therapies), prevention, and surveillance.