In the skin, basal epithelial cells constantly divide to renew the epidermis. The newly formed epithelial cells then differentiate in a process called keratinization, ultimately leading to the death of these cells and a pile-up of cell material containing vast amounts of keratins. The basal keratinocytes in skin are attached to their underlying basement membrane via specialized adhesion complexes termed hemidesmosomes (HDs). These complexes ascertain stable adhesion of the epidermis to the dermis, and mutations in components of these complexes often result in tissue fragility and blistering of the skin. In this review, we will describe the various hemidesmosomal proteins in detail as well as, briefly, the protein families to which they belong. Specifically, we will report the protein-protein interactions involved in the assembly of hemidesmosomes and their molecular organization. Some signaling pathways involving primarily the α6β4 integrin will be discussed, since they appear to profoundly modulate the assembly and function of hemidesmosomes. Furthermore, the importance of these hemidesmosomal components for the maintenance of tissue homeostasis and their involvement in various clinical disorders will be emphasized. Finally, we will present a model for the assembly of HDs, based on our present knowledge.