In healthy skin, a thin layer of tough keratinized epidermal cells protects the body from dehydration and attack by microorganisms. This protective barrier is built from basal skin cells, which proliferate and migrate upward from the lower (basal) skin layers. Researchers at the University of California at San Diego (CA) School of Medicine have now identified the essential trigger for this process—keratinocyte-differentiating factor, kDIF (Nature 410, 710–714, 2001). While studying the role of I-kappa-B kinase (IKK) in inflammation, Michael Karin and colleagues found that a catalytic subunit of the kinase, IKKα, regulated keratinocyte proliferation and differentiation. IKKα-knockout mice developed basal cell carcinomas, caused by the unchecked proliferation of basal skin cells, but at the time it was unclear why. The researchers suspected that a second factor was involved after grafting skin from IKKα-deficient mice onto wild-type controls. Though abnormal at first, IKKα-deficient skin soon acquired a normal appearance, indicating that a soluble factor was diffusing from the host skin. The molecular identity of kDIF is as yet unknown, but its discovery is a potential boon for the treatment of skin cancers and for tissue engineers hoping to create more functional skin grafts.