Epithelial cell plasticity is fundamentally required for cell differentiation during embryogenesis and contributes to metastatic cancer progression. Previously, we havediscovered a family of microRNAs (miR-200) that are critical regulators of epithelial-mesenchymal associated plasticity associated with invasive and stem-like properties (1,2). Sequencing of the transcriptome revealed that miR-200 causes widespread changes in alternative splicing, many of which are associated with reversal of epithelial-mesenchymal transition (EMT). By examining clinical and experimental datasets we identified the RNA binding protein, Quaking, as an important miR-200 target. Although Quaking has been implicated in alternative splicing its role in this process has not been well defined. Here, we show that Quaking regulates a large subset of alternative splicing events which are altered by miR-200 during EMT. In addition, reduction of Quaking expression phenocopies miR-200 function in attenuating cell migration and invasion. These data indicate that a miR-200-Quaking pathway operates to globally control EMT-associated alternative splicing. Further studies are directed at examining the functions of this pathway and alternatively spliced products in cancer progression.