The ileum has been candidate more frequently for endoscopic biopsy compared to the past. Most of those biopsies show either completely normal tissue or non-specific changes. Nevertheless, in some diseases, ileal biopsy would be diagnostic, and in some cases, it may be the only anatomical involved location by the disease. Endoscopically, normal mucosal biopsy is unlikely to provide useful diagnostic information and is not routinely recommended. However, in the presence of ileitis, ulcers, or erosions, biopsies can be very helpful. Ileitis might be induced by various conditions including infectious diseases, vasculitis, medication-induced, ischemia, eosinophilic enteritis, tumors etc. The conclusive cause of the condition is proposed by a comprehensive clinical background and physical examination, laboratory investigations, ileocolonoscopy, and imaging findings. Ileoscopy and biopsy are mainly useful in correctly selected cases such as patients who present with inflammatory diarrhea and endoscopic lesions. The purpose of this review article is to provide a simple algorithmic approach to the ileal biopsy samples through several boxes that give diagnostic clues and an idea behind the categories of ileal disorders.This review is written based on those that were previously reported in the literature as well as the authors' experiences. We have summarized different histological patterns in the ileal biopsy specimens that can be used in the diagnosis of inflammatory disorders of the ileum.This review provides an algorithmic approach to the clinicopathological features of inflammatory disorders of the ileum with a brief discussion of some important related issues.