Ovarian cancer is a highly invasive and metastatic disease with a poor prognosis if diagnosed at an advanced stage, which is often the case. Recent studies argue that ovarian cancer cells that have undergone epithelial to mesenchymal transition (EMT) acquire aggressive malignant properties, but the relevant molecular mechanisms in this setting are not well understood. Here we report findings from an siRNA screen that identified the homeobox transcription factor ALX1 as a novel regulator of EMT. RNAi-mediated attenuation of ALX1 expression restored E-cadherin expression and cell-cell junction formation in ovarian cancer cells, suppressing cell invasion, anchorage-independent growth and tumor formation. Conversely, enforced expression of ALX1 in ovarian cancer cells or non-tumorigenic epithelial cells induced EMT. We found that ALX1 upregulated expression of the key EMT regulator Snail (SNAI1) and that it mediated EMT activation and cell invasion by ALX1. Our results define the ALX1/Snail axis as a novel EMT pathway that mediates cancer invasion.