A number of different proteases and their inhibitors have a role in skin physiology and in the pathophysiology of inflammatory skin diseases. Proteases are important in the desquamation process and orderly regulation of the skin's barrier function. On the basis of the catalytic domain, proteases are classified into aspartate-, cysteine-, glutamate-, metallo-, serine-, and threonine proteases. Particularly, serine proteases (SPs) contribute to epidermal permeability barrier homeostasis, as acute barrier disruption increases SP activity in skin and inhibition by topical SP inhibitors accelerated recovery of barrier function after acute abrogation. In rosacea, increased levels of the vasoactive and inflammatory host-defense peptide cathelicidin LL-37 and its proteolytic peptide fragments were found, which were explained by an abnormal production of tryptic activity originating from kallikrein-related peptidase (KLK) 5. It is therefore possible that also other proteases, even from microbial or parasite origin, have a role in rosacea by forming alternate angiogenic and proinflammatory cathelicidin peptides. Further, the regulation of protease activity, in particular KLK-5 activity, might have a role in rosacea. This review briefly summarizes our current knowledge about keratinocyte-derived proteases and protease inhibitors, which might have a role in the pathophysiology of rosacea.