Hemidesmosomes are cell-substratum adhesion sites that connect the extracellular matrix to the keratin cytoskeleton. Our knowledge of the function of these structures has greatly increased as a result of studies on patients with aberrant expression of hemidesmosome components and studies using targeted inactivation of mouse genes encoding these components. Insight into the formation of hemidesmosomes, as well as into protein-protein interactions that occur in these junctional complexes, has recently been gained by in vitro cell transfections, blot overlay and yeast two-hybrid assays. In addition, recent results indicate that the alpha6 beta4 integrin is involved in the transduction of signals that are induced by the extracellular matrix and which modulate processes as diverse as cell proliferation, differentiation, apoptosis, migration and tissue morphogenesis. Thus it seems that hemidesmosomes do not merely maintain dermo-epidermal adhesion and tissue integrity, but that they are also implicated in intracellular signaling. Here we discuss recently published data on the biology and function of hemidesmosomes.