Ephrins and their Eph tyrosine kinase receptors control many processes during embryonic development. They have more recently also been identified as important regulators of proliferation of stem/progenitor cells in the adult brain and intestine and have been implicated in tumorigenesis in a large number of tissues. We here describe the expression of a large number of ephrins and Eph receptors in the adult mouse skin. Disruption of the ephrin-Eph interaction in vivo with antagonists against the A or B class resulted in an approximate doubling of cell proliferation in the hair follicle and epidermis of adult mice. We conclude that ephrins are negative regulators of proliferation in the skin and that blocking the ephrin-Eph interaction may be an attractive strategy for regenerative therapies.