The skin not only serves as a sensory organ, but also acts as a barrier that guards vertebrates from dehydration and infection. Skin integrity partly relies on the adhesion of the most basal keratinocytes to the underlying extracellular basal lamina. This attachment is mainly brought about by hemidesmosomes (HDs), which connect keratin intermediate filaments with the extracellular matrix. Now, Arnoud Sonnenberg and co-workers (te Molder et al., 2019) investigate the role of tetraspanin CD151, a known HD-associated protein, in the function of these adhesions. The authors show that CD151 binds to and colocalises with integrin α6β4 in peripheral and central adhesions. Notably, when CD151-deficient cells form new peripheral adhesions, integrin α6β4 is only maintained at the cell periphery, but not the cell centre. The authors show that these central adhesions display a hybrid molecular composition of HDs and tetraspanin-enriched microdomains (TEMs), and term them central HD-like adhesions. CD151 mediates the stability of central HD-like adhesions through both its interaction with integrin α3β1 and its ability to oligomerise and form multi-molecular complexes. Moreover, the maintenance of central HD-like adhesions requires the interaction of integrins α3β1 and α6β4 with their cognate ligand laminin-332. Collectively, these findings further our understanding of the functions of CD151 in keratinocyte adhesion and may provide insight into the skin blistering that is observed in patients carrying CD151 mutations.