Marfan syndrome is an autosomal dominant disorder of connective tissue due to abnormal fibrillin-1 caused by mutations in the FBN1 gene on chromosome 15. Affecting 1 in ≈5000 individuals, Marfan syndrome has widespread features involving the cardiovascular system, eye, skeleton, lung, dura, and skin. After evaluation of individuals and families with Marfan syndrome over the years, it is remarkable how variable the phenotype and age of onset of various manifestations may be among affected individuals, even in the same family. Some individuals with Marfan syndrome require aortic root replacement early in childhood, whereas others may not require aortic surgery until late in life, if at all. This highlights the importance of thorough screening of all first-degree relatives of the Marfan patient, long-term follow-up, and consideration of mutation analysis for those with ambiguous features. Article see p 526 The past 2 decades have witnessed remarkable scientific discovery and progress, providing hope to those affected by Marfan syndrome. In 1991, it was discovered that Marfan syndrome was due to a mutation in FBN1 , the gene that encodes fibrillin-1.1 Hundreds of different mutations in FBN1 have subsequently been described, with most families having their own private mutation. Because fibrillin-1 is present in tissues affected by Marfan syndrome, it was considered that the underlying defect in fibrillin-1 led to a primary structural weakness in this connective tissue protein. Because of recent discovery, this concept has come into question. Genetically engineered mouse models of Marfan syndrome, which recapitulate the phenotype observed in humans, have revolutionized understanding of basic pathophysiological mechanisms of this disease.2–4 Fibrillin-1 is a 350-kDa glycoprotein with multiple repeating, cysteine-rich, epidermal growth factor–like motifs, most of which are calcium binding. Fibrillin-1 also has motifs with homology to latent transforming growth factor-β–binding proteins. Fibrillin-1 proteins aggregate and associate to form microfibrils, …