Collagen is the fundamental building block of connective tissues found throughout the human body. A comprehensive understanding of the profound impact of collagen on skin health requires information about the molecule structure and the formation of a biaxial network within the plane of the skin. Collagen structure not only confers mechanical stability to tissues but also allows it to participate in a number of physiological processes. Topics discussed in this chapter include the importance of collagen assembly and organization in health and disease; structure and organization of collagen fibers in skin; role of collagen in skin mechanotransduction; proteoglycans in skin architecture; energy storage, transmission, and dissipation in skin; changes in collagen and proteoglycan composition in skin disorders; effects of genetic mutations; and association of fibrotic collagen with skin cancers. Skin-related diseases that are discussed include scleroderma, osteogenesis imperfecta, Ehlers-Danlos syndrome, epidermolysis bullosa, cutaneous lupus, Marfan syndrome, and dermatomyositis.