The hemidesmosome is a specialized transmembrane complex that mediates the binding of epithelial cells to the underlying basement membrane. In the skin, this multiprotein structure can be regarded as the chief adhesion unit at the site of the dermal-epidermal junction. Focal adhesions are additional specialized attachment structures located between hemidesmosomes. The integrity of the skin relies on well-assembled and functional hemidesmosomes and focal adhesions (also known as integrin adhesomes). However, if these adhesion structures are impaired, e.g., as a result of circulating autoantibodies or inherited genetic mutations, the mechanical strength of the skin is compromised, leading to blistering and/or tissue inflammation. A particular clinical presentation emerges subject to the molecule that is targeted. None of these junctional complexes are simply compounds of adhesion molecules; they also play a significant role in signalling pathways involved in the differentiation and migration of epithelial cells such as during wound healing and in tumour invasion. We summarize current knowledge about hereditary and acquired blistering diseases emerging from pathologies of the hemidesmosome and its neighbouring proteins as components of the dermal-epidermal junction.