Myc and transforming growth factor-β (TGFβ) signaling are mutually antagonistic, that is Myc suppresses the activation of TGFβ-induced genes, whereas TGFβ represses c-myc transcription. Here, we report a positive role for Myc in the TGFβ response, consisting in the induction of an epithelial-to-mesenchymal transition (EMT) and the activation of the EMT-associated gene Snail. Knockdown of either Myc or the TGFβ effectors SMAD3/4 in epithelial cells eliminated Snail induction by TGFβ. Both Myc and SMAD complexes targeted the Snail promoter in vivo, DNA binding occurring in a mutually independent manner. Myc was bound prior to TGFβ treatment, and was required for rapid Snail activation upon SMAD binding induced by TGFβ. On the other hand, c-myc downregulation by TGFβ was a slower event, occurring after Snail induction. The response of Snail to another cytokine, hepatocyte growth factor (HGF), also depended on Myc and SMAD4. Thus, contrary to their antagonistic effects on Cip1 and INK4b, Myc and SMADs cooperate in signal-dependent activation of Snail in epithelial cells. Although Myc also targeted the Snail promoter in serum-stimulated fibroblasts, it was dispensable for its activation in these conditions, further illustrating that the action of Myc in transcriptional regulation is context-dependent. Our findings suggest that Myc and TGFβ signaling may cooperate in promoting EMT and metastasis in carcinomas.