The skin is the largest organ of the body and the first barrier to protect the organism against the external environment. The skin is organized in three layers: epidermis, dermis, and hypodermis. The largest component of skin is the extracellular matrix (ECM), which is composed of collagens, elastin fibers, glycoproteins, and matricellular proteins found in the epidermis and dermis. The ECM plays an important role in regulating and ensuring skin homeostasis; however, deregulation in ECM composition contributes to the development of skin diseases. The most common skin diseases are atopic dermatitis, hidradenitis suppurativa, psoriasis, urticaria, vitiligo, and alopecia, while less common examples are prurigo nodularis, scleroderma, and systemic lupus erythematosus. ECM biomarkers have been associated with the severity and activity of different skin diseases and may be valuable for diagnostic and prognostic purposes.