Thoracic aortic aneurysms and dissections (TAADs) involve dilation of the aortic wall that can lead to tearing or rupture. Progressive extracellular matrix (ECM) degradation is common in TAAD, regardless of the underlying cause. TAAD treatments typically target cellular signaling pathways, rather than the ECM itself, due to the complex assembly process and long half-life of ECM proteins. Compounds that stabilize the ECM are proposed as an alternative TAAD therapy that addresses the underlying cause of aortic wall failure, namely compromised structural integrity. Compounds are discussed that revisit historical approaches to maintain and preserve structural integrity of biological tissues.