The evaluation of patients with colitis of recent onset is a relatively common clinical challenge. The main considerations are infectious colitides, idiopathic IBD, ie, ulcerative and Crohn’s colitis, and colonic ischemia. An initial risk assessment on the basis of such factors as concurrent symptoms in contacts, travel history, medications, and human immunodeficiency virus risk factors should be followed by a thorough clinical history, physical examination, stool studies, blood tests, and, in selected cases, endoscopic examination and serologic tests. Biopsies can be decisive in distinguishing among the different types of acute colitis and might help identify specific etiologies. The diagnostic yield of biopsies is maximized by appropriate sampling of the colonic mucosa and by sharing the clinical and endoscopic findings with the pathologist, eg, via a copy of the endoscopy report.