Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development， as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here， we show that TPL2 overexpression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically， activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK， mTOR， NF-κB， and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly， TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance， validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally， we verified that TPL2 is overexpressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together， our results establish TPL2 as an oncogenic driver in SCC/KA development. Cancer Res; 76(22); 6712-22. ©2016 AACR.