Hic-5 up-regulation during TGF-β–stimulated EMT promotes the development of an invasive phenotype through activation of multiple signaling pathways. TGF-β treatment results in the increased expression of Hic-5. Src is phosphorylated in response to Hic-5 expression, and Src activity is necessary for the phosphorylation of Hic-5, resulting in a positive feedback activation of Src. TGF-β–stimulated ROCK-mediated matrix degradation is downstream of Hic-5 expression and requires RhoC, but not RhoA. Hic-5 up-regulation also stimulates the activation of Rac1–p38 MAPK, which is also required for the invasive phenotype including invadopodia formation, matrix degradation, and increased invasion.