Author SummaryGDP/GTP exchange factors (GEFs) involved in Rho GTPase activation have been traditionally considered as potential anticancer drug targets. However, little is known about the best GEFs to inhibit in different tumor types, the pro-tumorigenic programs that they regulate, and the collateral effects that inactivation may induce in healthy tissues. Here, we investigate this issue in HRas-dependent skin tumors using genetic techniques. Despite the large number of Rho GEFs present in both normal and tumoral epidermis, we demonstrate that the co-expression of the exchange factors Vav2 and Vav3 is critical for the development of this tumor type. We also identify a previously unknown Vav-dependent autocrine/paracrine program that favors keratinocyte survival/proliferation and the formation of an inflammatory state during the initiation and promotion phases of this tumor. Finally, our results indicate that inactivation of Vav proteins is innocuous for the homeostasis of normal epidermis. Taken together, these results imply that Vav protein-based therapies may be of interest for skin tumor prevention and/or treatment.