In many tissues microtubules reorganize into non-centrosomal arrays in differentiated cells. In the epidermis, proliferative basal cells have a radial array of microtubules organized around a centrosome, while differentiated cells have cortical microtubules. The desmosomal protein desmoplakin is required for the microtubules to organize around the cell cortex. Furthermore, the centrosomal and/or microtubule-associated proteins ninein, Lis1, Ndel1, and CLIP170 are recruited to the cell cortex, where they have been implicated in the cortical organization of microtubules. Recently, it has been shown that in Lis1-null epidermis, microtubules are disorganized in the differentiated layers of the epidermis. Furthermore, Lis1-null mice die perinatally due to dehydration. This is due, in part, to the unexpected desmosome phenotype observed in Lis1-null skin. Upon loss of Lis1, desmosomal proteins become less stable. Here, we propose that Lis1 may regulate desmosomal stability through its binding partners Nde1/Ndel1 and dynein.