Matrix metalloproteinases (MMPs) are thought to contribute to excessive proteolysis and impaired remodelling of chronic wound wounds. However, in recent years, it has become clear that MMPs play an important role in chemokine regulation, resolution of inflammation, and positive remodelling. This prompted us to evaluate the role of other proteases in tissue injury, inflammation and repair. Granzymes are a family of five serine proteases that were once believed to exert redundant roles in cytotoxic lymphocyte-induced apoptosis. The dogma being that granzymes are released by CTL/NK cells towards the target cell, along with the pore-forming protein perforin that facilitates target cell internalization, to induce apoptosis. However, in recent years this concept has been challenged. It is now recognized that granzymes are not redundant, exert non-cytotoxic roles, can be expressed and secreted by different types of immune and non-immune (eg. Keratinocytes) cells, accumulate and retain activity in the extracellular milieu. Granzyme B (GzmB) is the most widely studied of the granzymes. Previous work in numerous age-related and/or autoimmune skin conditions have reported elevated GzmB with the presumption that GzmB contributes to apoptosis. Based on the aforementioned new knowledge pertaining to GzmB (and other granzymes), the role of granzymes in skin inflammation must be revisited. Degradomic approaches to identify GzmB substrates in skin combined with protease assays to confirm substrates, immunohistochemical and functional analyses suggest that GzmB contributes to sub-epidermal blistering and/or loss of epidermal barrier function depending on the source and location of the protease. The present talk will focus on newly discovered roles for granzymes in reduced epithelial barrier function, extracellular matrix cleavage, blistering and impaired remodelling.