The skin's barrier function is primarily maintained by the cohesion of its layers and the specialized stratum corneum. Genetic and autoimmune disorders that result in skin fragility have significantly contributed to understanding the role of various molecular components in the skin. These conditions, characterized by blisters, erosions, wounds, and impaired wound healing, are rare but must be considered in clinical differential diagnoses. Key cutaneous adhesion structures include the epidermal basement membrane, anchoring fibrils, cell-matrix adhesions (e.g., hemidesmosomes and focal adhesions), and cell-cell adhesions (e.g., desmosomes and corneodesmosomes). These multiprotein suprastructures not only provide structural support but also participate in signaling processes and physiological or pathological conditions such as skin aging and wound healing. Additionally, dermal connective tissue plays a structural role and serves as a reservoir for proteases, growth factors, and cytokines. Modern techniques like single-cell and spatial transcriptomics, combined with artificial intelligence algorithms, are advancing the molecular mapping of human skin. Moreover, this review highlights the molecular composition of adhesion structures and the specific diseases associated with deficiencies in these components.