Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium-binding extracellular matrix glycoprotein encoded by the FBN1 gene. It is a structural component of microfibrils and provides mechanical support in elastic and nonelastic connective tissues. Mutations in the FBN1 gene can cause a variety of genetic diseases, including Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal, and cardiovascular abnormalities. FBN1 interacts with numerous microfibril-associated proteins, growth factors, and cell membrane receptors, mediating a wide range of biological processes such as cell survival, proliferation, migration, and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders, and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. This review summarizes the structure and expression of FBN1 and presents the current understanding of its functional role in various human diseases. This knowledge will allow the development of better strategies for therapeutic intervention of FBN1-related diseases. FBN1 is a large protein with 350 kDa in size. It serves as the primary structural constituent of microfibrils of 10–12 nm in diameter, which are ubiquitously present in all connective tissues. The human FBN1 gene resides on chromosome 15 long arm (15q15-21.1), spans about 230 kb genomic DNA, and is highly split into 65 exons, and codes for a protein with 2871 amino acids. The structure of FBN1 consists of 47 six-cysteine EGF-like and 7 eight-cysteine TGF-β binding protein-like (TB) domains. Among the 47 EGF domains, 43 of these domains exhibit the occurrence of a calcium binding consensus sequence, hence being referred to as calcium binding EGF-like domains. The cbEGF domain performs a supportive role through limiting the mobility of interdomain areas and protecting molecules from proteolysis. These cbEGF domains also interact with FBN2, as well as with other ECM proteins, such as fibulin-2, -4, -5, heparin, microfibril-associated glycoprotein (MAGP)-1, aggrecan, and versican. The disulfide bond that arises from the interaction between the six cysteine residues present within EGF and cbEGF is helpful to stabilize FBN1. The cbEGF domain is observed to occur in numerous copies, and in the majority of instances, each cluster of cbEGF repeats is distinctly differentiated from the subsequent cluster by means of the TB domain. Furthermore, apart fromFibrillin-1 (FBN1) is a large, cysteine-rich, calcium-binding extracellular matrix glycoprotein encoded by the FBN1 gene. It is a structural component of microfibrils and provides mechanical support in elastic and nonelastic connective tissues. Mutations in the FBN1 gene can cause a variety of genetic diseases, including Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal, and cardiovascular abnormalities. FBN1 interacts with numerous microfibril-associated proteins, growth factors, and cell membrane receptors, mediating a wide range of biological processes such as cell survival, proliferation, migration, and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders, and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. This review summarizes the structure and expression of FBN1 and presents the current understanding of its functional role in various human diseases. This knowledge will allow the development of better strategies for therapeutic intervention of FBN1-related diseases. FBN1 is a large protein with 350 kDa in size. It serves as the primary structural constituent of microfibrils of 10–12 nm in diameter, which are ubiquitously present in all connective tissues. The human FBN1 gene resides on chromosome 15 long arm (15q15-21.1), spans about 230 kb genomic DNA, and is highly split into 65 exons, and codes for a protein with 2871 amino acids. The structure of FBN1 consists of 47 six-cysteine EGF-like and 7 eight-cysteine TGF-β binding protein-like (TB) domains. Among the 47 EGF domains, 43 of these domains exhibit the occurrence of a calcium binding consensus sequence, hence being referred to as calcium binding EGF-like domains. The cbEGF domain performs a supportive role through limiting the mobility of interdomain areas and protecting molecules from proteolysis. These cbEGF domains also interact with FBN2, as well as with other ECM proteins, such as fibulin-2, -4, -5, heparin, microfibril-associated glycoprotein (MAGP)-1, aggrecan, and versican. The disulfide bond that arises from the interaction between the six cysteine residues present within EGF and cbEGF is helpful to stabilize FBN1. The cbEGF domain is observed to occur in numerous copies, and in the majority of instances, each cluster of cbEGF repeats is distinctly differentiated from the subsequent cluster by means of the TB domain. Furthermore, apart from