Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism governing the switch of cells from an epithelial to a motile mesenchymal-like state. This transdifferentiation is regulated by key transcription factors, including Slug. The stability and function of Slug can be regulated by multiple mechanisms, including ubiquitin-mediated post-translational modifications. Here, by using a genome wide siRNA screen for human deubiquitinating enzymes (DUBs), we identified USP10 as a deubiquitinase for Slug in cancer cells. USP10 interacts with Slug and mediates its degradation by the proteasome. Importantly, USP10 is concomitantly highly expressed with Slug in cancer biopsies. Genetic knockdown of USP10 leads to suppressed Slug levels with a decreased expression of the mesenchymal marker Vimentin. Further, it reduces the migratory capacity of cancer cells. Reversely, overexpression of USP10 elevates the level of both Slug and Vimentin. Our study identifies USP10 as a regulator of the EMT-transcription factor Slug and cell migration.