Despite considerable research effort, there is no widely accepted method for the purification of epidermal stem cells. On p. 4239, Hong Wan and co-workers report a new strategy for the isolation of these cells that combines selection for low levels of expression of the desmosomal cadherin desmoglein 3 (Dsg3) with high levels of β1 integrin, a previously proposed marker for epidermal stem cells. Because desmosomes become more numerous as keratinocytes differentiate, the researchers hypothesised that these intracellular junctions might be sparse in epidermal stem cells. They confirmed this by colony-formation assays of keratinocytes sorted on the basis of desmosomal protein expression. Keratinocyte populations that have high levels of β1 integrin and low levels of Dsg3 were more enriched for stem-cell-like cells than were keratinocytes selected with either marker alone. This strategy for epidermal stem-cell enrichment, they conclude, should be useful both for stem-cell studies and for the development of stem-cell-mediated replacement therapies.