The Raf/MEK/ERK cascade is a highly conserved signal transduction module whose activation reportedly results in a plethora of physiological outcomes. Depending on the cell type or the stimulus used, the pathway has been implicated in proliferation, differentiation, survival, and migration. Their wide range of activities renders the component of the Raf/MEK/ERK pathway prime candidates for molecule-targeted therapies, in particular, but not exclusively, in the context of cancer. Ras, Raf and MEK inhibitors have been developed, and some of them are in advanced clinical trials. Somewhat surprising in view of all this interest, our understanding of the fundamental biology of the ERK pathway in vivo is still scanty. Its investigation has been hampered by the fact that conventional targeting of many of these genes results in embryonic lethality. Recently, we and others have generated mouse strains that allow the conditional ablation of the genes coding for Raf-1, B-Raf and MEK-1. We are using these tools to identify the essential biological functions of these kinases, and to understand how the ERK pathway is wired in vivo. Here, we discuss some of the surprises yielded by the analysis of the role of B-Raf and Raf-1 and of their downstream effectors. Œ2006 Landes Bioscience.