Fibrillins 1 and 2 are the main constituents of the extracellular microfibrils responsible for the biomechanical properties of most tissues and organs. They are cysteine-rich glycoproteins predominantly made of multiple repeats homologous to the calcium-binding epidermal growth factor module, and are translated as precursor proteins cleaved by furine/PACE-like activities. Fibrillins polymerize extracellularly as parallel bundles of head-to-tail monomers. Binding to calcium rigidifies the structure of the monomers and the supramolecular organization of the macroaggregates. Fibrillin-1 mutations result in the pleiotropic manifestations of Marfan syndrome, and fibrillin-2 alterations cause the overlapping phenotype of congenital contractural arachnodactyly. It is hypothesized that fibrillin-2 guides elastogenesis, whereas fibrillin-1 provides force-bearing structural support. Gene targeting work in the mouse is shedding new light on their distinct and overlapping contributions to tissue morphogenesis and homeostasis. It is also providing an animal model in which to test therapies aimed at reducing hemodynamic stress and the collapse of the aortic matrix during dissecting aneurysm.