Mitogen- and stress-activated protein kinase (MSK)1/2 are two kinases involved in inflammation as well as in cell transformation. Purpose: To examine the role of MSK1/2 in skin tumor development. Results: MSK1/2 knockout mice developed significantly fewer skin tumors compared with wild-type mice. The myeloperoxidase activity in TPA-treated skin from MSK1/2 knockout mice was significantly elevated compared with wild-type mice. Furthermore, the mRNA and protein levels of IL-1 beta beta as well as the mRNA expression of TNF-alpha alpha were significantly increased in MSK1/2 knockout mice. Conclusion: These data provide in vivo evidence that MSK1/2 signaling represents a novel tumor-promoting axis in skin carcinogenesis.</.