Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium-binding extracellular matrix glycoprotein encoded by the *FBN1* gene. It serves as a structural component of microfibrils, providing mechanical support in elastic and non-elastic connective tissues. Mutations in the *FBN1* gene can cause a wide range of genetic diseases, including Marfan syndrome, characterized by ocular, skeletal, and cardiovascular abnormalities. FBN1 interacts with numerous microfibril-associated proteins, growth factors, and cell membrane receptors, mediating various biological processes such as cell survival, proliferation, migration, and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, including 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. This review summarizes the structure, expression, and functional role of FBN1 in various human diseases, highlighting its potential as a therapeutic target.Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium-binding extracellular matrix glycoprotein encoded by the *FBN1* gene. It serves as a structural component of microfibrils, providing mechanical support in elastic and non-elastic connective tissues. Mutations in the *FBN1* gene can cause a wide range of genetic diseases, including Marfan syndrome, characterized by ocular, skeletal, and cardiovascular abnormalities. FBN1 interacts with numerous microfibril-associated proteins, growth factors, and cell membrane receptors, mediating various biological processes such as cell survival, proliferation, migration, and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, including 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. This review summarizes the structure, expression, and functional role of FBN1 in various human diseases, highlighting its potential as a therapeutic target.