The skin, as a barrier organ meeting constant mechanical challenges, is equipped with multiple adhesive structures that collectively support resilient, yet flexible attachment of its epithelium -the epidermis to its mesenchyme - the dermis. One such structure is the collagen VII-composed anchoring fibril, which provides firm anchorage of the epidermal basement membrane to the underlying interstitial extracellular matrix. Blistering and wider tissue fragility in the genetic disease dystrophic epidermolysis bullosa (DEB) caused by collagen VII deficiency illustrate the essential function of collagen VII in supporting skin integrity. DEB is also a progressive inflammatory fibrotic disease with multi-organ involvement, indicating that collagen VII has broader functions than simply providing epithelial anchorage. This review explores the reciprocal relationship between collagen VII biology and DEB pathophysiology. A deeper understanding of collagen VII biology - spanning its synthesis, assembly into suprastructures, and regulatory roles - enhances our understanding of DEB. Conversely, detailed insights into DEB through analysis of disease progression or therapeutic interventions offer valuable information on the broader tissue and organismal roles of collagen VII in maintaining homeostasis. This review focuses on such knowledge exchange in advancing our understanding of collagen VII, the extracellular matrix in general, and inspiring potential strategies for treatment of DEB. Importantly, in a broader sense, the discussed themes are applicable to other conditions driven by compromised extracellular matrix instruction and integrity, leading to progressive damage and inflammation.