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Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; <i>P</i> = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.