Acutely ill medical patients may be at increased risk of venous thromboembolism, both during hospitalization and after discharge. International guidelines recommend thromboprophylaxis for high-risk medical patients with low bleeding risk for a maximum of 14 days. There are two approaches to identify the high-risk patient: adhering to the inclusion criteria used in randomized clinical trials or using risk assessment models. With both approaches, about 40% of medical inpatients should result at increased risk of venous thrombosis. However, in the real world, medical inpatients are more fragile than patients enrolled in clinical trials, and thus also require a careful assessment of the individual bleeding risk. The complex balance between risks and benefits of thromboprophylaxis has become particularly relevant in studies assessing extended prophylaxis beyond hospitalization in this setting. In the present review, we will summarize the most recent evidence on this topic.