Current guidelines on the treatment of acute pulmonary embolism (PE) recommend stratification of hemodynamically stable patients in ‘low risk’ and ‘intermediate risk’. Validated risk scores, cardiac biomarkers, and imaging of the right ventricle all help in distinguishing both patient categories. The relevance of this risk stratification lies in the determination of the most optimal treatment for the individual patient. In this clinical review, we will discuss how patients with ‘intermediate-risk’ PE can be identified as well as recent advances in their therapeutic management. Based on a clinical case, we will highlight the indications for reperfusion therapy and the current experience with non-vitamin K-dependent oral anticoagulant (NOACs) in this specific patient's category.