The Ras/Raf/Mek/Erk pathway represents the oldest paradigm of a cytosolic signal transduction cascade, and its constitutive activation is a key event in the development of several human malignancies and developmental disorders. Understandably, the search for inhibitors of pathway components has been raging on for the last decade. Several compounds have been evaluated in phaseI/II studies, but robust clinical proof of concept for the benefits of single-agent therapy targeting the Erk pathway is still lacking. Recently, inhibitors developed against the mutant form of B-Raf most frequently observed in human melanoma (B-Raf V600E) have shown sensational results, with 70% of the melanoma patients responding to the drug. Prominent among the side effects, however, is the development of drug-related cutaneous squamous cell carcinomas. Irrespectively of the irrefutable benefit of the drug for the patients, this sounds a note of caution for the use of B-Raf inhibitors. Indeed, these substances have been shown to activate another Raf kinase, C-Raf, either directly or by an indirect mechanism involving complex formation between B- and C-Raf. Thus, paradoxically, Raf inhibitors can activate the Erk pathway, possibly deregulating proliferation and promoting the development of therapy-related tumors. We have used a mouse model of Ras-driven squamous cell carcinoma coupled to epidermis-restricted knock-out of B-Raf, C-Raf, or both, to analyze the effect of chemical and endogenous Raf and MEK inhibitors on tumor development. The results of this analysis have yielded mechanistic insight in the relationship between Ras, B-/C-Raf, and the Erk pathway in the epidermis and in the mode of action of Raf inhibitors.