Acute medical illnesses are associated with a prolonged elevation in inflammatory markers that predisposes patients to thrombosis beyond the duration of their hospital stay. In parallel, both observational and randomized data have demonstrated a rate of postdischarge venous thromboembolic events that often exceeds that observed in the hospital setting. Despite this significant residual risk of venous thromboembolic events following discharge among acute medically ill patients, no therapeutic strategies have been recommended to address this unmet need. Available randomized trials have demonstrated the efficacy of extending the duration of thromboprophylaxis with available anticoagulants; however, the efficacy is offset, at least in part, by an increase in bleeding events. Identification of the optimal therapeutic strategies, treatment duration, and risk assessment tools that reconcile both efficacy and safety of extended-duration thromboprophylaxis among acute medically ill patients is an area of ongoing investigation.