The balance between proteases and protease inhibitors plays a critical role in tissue remodeling during cardiovascular diseases. Different serine protease inhibitors termed serpins, which are expressed in the cardiovascular system, can exert a fine-tuned regulation of protease activities. Among them, protease nexin-1 (PN-1, encoded bySERPINE2) is a very powerful thrombin inhibitor and can also inactivate plasminogen activators and plasmin. Studies have shown that this serpin is expressed by all cell subpopulations in the vascular wall and by circulating cells but is barely detectable in plasma in the free form. PN-1 present in platelet granules and released upon activation has been shown to present strong antithrombotic and antifibrinolytic properties. PN-1 has a broad spectrum of action related to both hemostatic and blood vessel wall protease activities. Different studies showed that PN-1 is not only an important protector of vascular cells against protease activities but also a significant actor in the clearance of the complexes it forms with its targets. In this context, PN-1 overexpression has been observed in the pathophysiology of thoracic aortic aneurysms (TAA) and during the development of atherosclerosis in humans. Similarly, in the heart, PN-1 has been shown to be overexpressed in a mouse model of heart failure and to be involved in cardiac fibrosis. Overall, PN-1 appears to serve as a “hand brake” for protease activities during cardiovascular remodeling. This review will thus highlight the role of PN-1 in the cardiovascular system and deliver a comprehensive assessment of its position among serpins.