Updated project metadata. The resistance of cancer cell to therapy is responsible of the death of most cancer patients. Epithelial to mesenchymal transitions (EMT) has been associated with resistance to therapy in different cancer cells. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma (SCC) undergoing spontaneous EMT during tumorigenesis, we identified EMT tumor subpopulations displaying different intrinsic resistance mechanisms to a wide range of anti-cancer therapy both in-vivo and in-vitro. We found that RhoJ, a small GTPase, preferentially expressed in EMT cancer cells controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling combined with functional assays following loss of RhoJ functions, we found that RhoJ regulated EMT associated resistance to chemotherapy by promoting DNA damage response and the formation of new replication forks allowing EMT tumor cells to repair DNA lesions more rapidly and survive under the replicative stress induced by chemotherapy. Altogether, our study uncovers RhoJ as a key regulator of EMT associated resistance to chemotherapy with important implications for the development of new strategies to overcome resistance to therapy in cancer.