While systemic intravenous thrombolysis decreases mortality in patients with high-risk pulmonary embolism (PE), it clearly increases haemorrhagic risk. There are many contraindications to thrombolysis, and efforts should aim at selecting those patients who will benefit most, without suffering complications. The current review summarises the evidence for the use of thrombolytic therapy in PE. It clarifies the pathophysiological mechanisms in PE and acute cor pulmonale that increase the risk of bleeding following thrombolysis. It discusses future management challenges, namely tailored drug administration, new treatment monitoring techniques and catheter-directed thrombolysis.