Venous thromboembolism that occurs in unusual sites is challenging because of the potential severity of presentation, the presence of some major provoking risk factors, the high prevalence of potential contraindications to antithrombotic therapies, the lack of solid evidence to guide therapeutic decisions, and because of the severity of long-term consequences. For example, venous thrombosis in the splanchnic veins frequently occurs in patients with liver cirrhosis. Not uncommonly, these patients present with concomitant active gastrointestinal bleeding, and/or low platelet count or oesophageal varices. If inadequately treated, splanchnic vein thrombosis (SVT) may further worsen portal hypertension and, thus, increase the long-term risk of bleeding. Up to 40% of patients with cerebral vein thrombosis (CVT) have signs of intracranial bleeding at the time of the diagnosis. This finding is associated with worst prognosis in terms of death or severe disability. Despite the apparent presence of a major contraindication to anticoagulation, only a timely administration of parenteral anticoagulant drugs may improve this unfavourable outcome. The available evidence on the management of these two challenging disorders, SVT and CVT, will be reviewed in this article.