The extracellular matrix (ECM) is a complex entity with structural proteins (such as fibrillins, collagen, elastin), ground substance (proteoglycans), modifying enzymes (ADAMTS, PLOD, lysyloxidases (LOX)) and cytokines that regulate morphogenesis, growth, homeostasis and repair (transforming growth factor-beta [TGF-beta], bone morphogenic protein [BMP]). Over the last decade, the intimate relationship between structural proteins and these growth factors has emerged. The study of the extracellular matrix in human conditions and relevant mouse models is gradually unmasking the key role of these structural molecules in the regulation of the bio-availability of these growth factors. Major progress has been made in the study of the cardiovascular system (1) and the first clues in the skeletal system have emerged. (2) In this review, we will discuss the clinical, molecular, and pathogenic aspects of Marfan syndrome, Loeys-Dietz syndrome and related disorders with emphasis on the role of fibrillins and TGF-beta.