Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects over 600,000 individuals in the United States and accounts for 5--10% of end-stage renal disease. Currently, there are no preventative treatments. 85% of the ADPKD patients have mutations in the gene polycystin-1 (PC1), which we have previously shown to interact with the protein signal transducer and activator of transcription (STAT) 6. Here we show that STAT6 is activated in cystic epithelia from mouse models, that STAT6 is part of a positive feedback loop, and that genetic removal or pharmacological inhibition of STAT6 reduces disease. Interleukin-13 (IL13), which we found highly expressed in cyst fluid, is sufficient to induce expression of several genes, including periostin, galectin-3 and IL24 in kidney epithelial cells, with STAT6 being necessary for periostin expression. Inhibition of IL13 or the IL13 receptor using protein compounds proved unsuccessful in decreasing disease, most likely due to their inability to access the cystic space. A potential solution is to exploit...(embargoed)...therapies may not.