Kallikrein-related peptidase 6 (KLK6) is a serine protease that is aberrantly altered in various types of cancer, but its role in non-melanoma skin cancer has not been investigated. KLK6 is active in epidermis and has been linked to normal skin differentiation. Thus, we investigated whether it could be implicated in skin tumorigenesis in vivo. Carcinogenesis was induced in Klk6^−/− mice by epidermal application of 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate (DMBA/TPA), and multistage skin tumor development and progression was monitored closely until squamous cell carcinomas (SCCs) and invasive tumors formed. Klk6^−/− (but also Klk6^+/−) mice were highly resistant to tumor growth/development manifested by their highly diminished numbers and delayed onset of tumors compared with wild-type (wt) mice. Histological analyses of the few tumors that developed in Klk6^−/− after prolonged (>1 year) chemical challenge revealed that these were mainly benign papillomas, whereas in wt mice tumors progressed to SCCs. Inflammation was attenuated in Klk6^−/− skin following chronic exposure to TPA, indicated by markedly low expression of proinflammatory cytokines, in direct contrast to wt. Further, in Klk6^−/− mice, the ability of implanted nascent PDVC57 skin cancer cells to form tumors was highly diminished. Our study identified KLK6 as a new tumor-promoting factor of early skin cancer and suggested that KLK6 is an important molecular link in the development of skin inflammation and in tumor-promoting inflammatory processes.