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The transforming growth factor-beta (TGF-β) signaling pathway regulates biological processes critical to embryonic development and tissue homeostasis, including cell proliferation, differentiation, adhesion and migration. Perturbations in TGF-β signaling are linked to a wide range of human diseases, including those affecting the cardiovascular system. This review summarizes decades-long evidence documenting the importance of this pathway to hereditary forms of aortic disease and presents current perspectives on its role in pathogenesis. We discuss the dual role of TGF-β signaling in aneurysm progression, and its protective and maladaptive effects on vascular smooth muscle cells (VSMCs) phenotype, extracellular matrix (ECM) composition, and other disease-relevant signaling pathways.