The biosynthetic pathway for the fibrillar collagens expressed in skin, identifying steps that are affected in different forms of EDS. (I) Collagen gene transcription is highly regulated, but haploinsufficiency for COL5A1 is uncompensated and leads to a reduction in COL5A1 mRNA and α1(V) procollagen chains. This accounts for 30–50% of classical EDS cases. (II) Many proline and lysine residues in the translated procollagen chains are hydroxylated by lysyl- and proline hydroxylases. Hydroxylation is essential for subsequent crosslinking and lysyl-hydroxylase deficiency causes the kyphoscoliosis form of EDS. (III) Procollagen α-chains are assembled into trimers within the rough endoplasmic reticulum (RER). Mutations in COL3A1 that interrupt the triple helical structure prevent normal processing and secretion of collagen III, causing the vascular form of EDS. (IV) In the ECM, the NH₂- and COOH-terminal propeptides are cleaved by specific peptidases. Dominant mutations in COL1A1 and COL1A2 can prevent cleavage and cause arthrochalasia, while recessive loss of the N-procollagen peptidase cause dermatosparaxis. (V) Collagen molecules self-assemble into heterotypic fibrils. Dominant-negative mutations in COL5A1 and COL5A2 alter fibril assembly and cause some cases of classical EDS. (VI) Collagen fibrils are deposited in tissue-specific arrangements in close association with many fibril-associated proteins and proteoglycans. Because new fibrils are laid down in close association with the fibroblast cell membrane, interactions between the fibril and the cell are important and may involve direct interaction with collagens and/or matricellular proteins, including tenascin-X (TNX).