SUMMARY Metastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics, such as invasion, metastasis and stemness. To better understand the post-translational regulation of SNAIL, we performed a luciferase-based genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 which targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Serine-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of post-translational regulation of EMT and cancer metastasis.