Toxic megacolon represents a dreaded complication of mainly inflammatory or infectious conditions of the colon. It is most commonly associated with inflammatory bowel disease (IBD), i.e., ulcerative colitis or ileocolonic Crohn's disease. Lately, the epidemiology has shifted toward infectious causes, specifically due to an increase of Clostridium difficile-associated colitis possibly due to the extensive (ab)use of broad-spectrum antibiotics. Other important infectious etiologies include Salmonella, Shigella, Campylobacter, Cytomegalovirus (CMV), rotavirus, Aspergillus, and Entameba. Less frequently, toxic megacolon has been attributed to ischemic colitis, collagenous colitis, or obstructive colorectal cancer. Toxic colonic dilatation may also occur in hemolytic-uremic syndrome (HUS) caused by enterohemorrhagic or enteroaggregative Escherichia coli O157 (EHEC, EAEC, or EAHEC). The pathophysiological mechanisms leading to toxic colonic dilatation are incompletely understood. The main characteristics of toxic megacolon are signs of systemic toxicity and severe colonic distension. Diagnosis is made by clinical evaluation for systemic toxicity and imaging studies depicting colonic dilatation. Plain abdominal imaging is still the most established radiological instrument. However, computed tomography scanning and transabdominal intestinal ultrasound are promising alternatives that add additional information. Management of toxic megacolon is an interdisciplinary task that requires close interaction of gastroenterologists and surgeons from the very beginning. The optimal timing of surgery for toxic megacolon can be challenging. Here we review the latest data on the pathogenesis, clinical presentation, laboratory, and imaging modalities and provide algorithms for an evidence-based diagnostic and therapeutic approach.