Keratinocyte proliferation and differentiation is regulated via proteolytic networks. Dysregulation of proteases within these systems can cause hyperproliferative and inflammatory skin disorders. In healthy skin the metalloprotease meprin α is localized in the stratum basale, yet in wound healing tissue and psoriatic lesions meprin α is synthesized at higher levels and translocalized to upper epidermal layers. We developed a transgenic mouse model for inducible expression of pathological meprin α levels (K5Mα) to investigate its epidermal degradome and, thereby, identify molecular links to keratinocyte proliferation and skin inflammation.