Hemidesmosomes are rivet-like complexes that anchor epithelial cells to the extracellular matrix (ECM), physically linking it to the cell's cytoskeleton. They contain at least five proteins: integrin α6β4, which is central to the complex and binds to laminin 5 in the ECM; plectin, a plakin that connects the complex to keratin intermediate filaments; bullous pemphigoid antigen 230 (BP230), another plakin; BP180; and CD151. Arnoud Sonnenberg and co-workers have examined how these components fit together, combining exhaustive two-hybrid analysis with assessment of the ability of point mutants to complement genetic deficiencies in keratinocytes (see p. 387). This has allowed them to map pairwise interactions between the integrin, plectin, BP180 and BP230. The studies also reveal a hierarchical assembly mechanism of unanticipated complexity. For example, although BP230 can interact with both α6β4 and BP180, plectin is required for incorporation of BP180, and recruitment of BP230 occurs only if BP180 is present. These findings allow the authors to propose an assembly model in which the integrin first interacts with plectin, which unfolds its cytoplasmic domain, and BP180 and BP230 are then recruited sequentially.