The overarching goal of our Leducq International Network of Excellence (INE) is to prevent dissection-related deaths and disability by identifying molecular changes in the aortic wall that trigger dissections and using these data to discover novel biomarkers and therapeutics that reliably predict and effectively prevent acute aortic dissections. Based on novel cell-specific analyses of aortic tissue samples from patients with aortic disease and control subjects, we hypothesize that the major cells in the aortic wall, smooth muscle cells, over-activate cellular motors, which increases energy production by the cells. As additional cell pathways are activated, the cells eventually fail and cannot maintain these compensatory changes, triggering cell death and dissection. Inflammation in the aortic wall also appears to contribute to dissection. Rigorous testing of this hypothesis using several mouse models of dissection that reflect known risk factors for the disease will identify critical changes in cells; these will then be validated in patients’ aortic tissue samples and targeted with therapeutics to prevent dissections. The most promising drugs will be assessed in all dissection mouse models in preparation for patient clinical trials. Finally, we propose innovative studies to address a critical tool missing in the clinical management of at-risk patients: a reliable biomarker to indicate an imminent risk for a dissection. Together, this INE will work to make substantial progress toward preventing premature deaths due to acute aortic dissections.