The present invention is directed to methods of treating or ameliorating an effect of a polycystic disease. More particularly, the methods include administering to a patient in need thereof an amount of a modulator of a tumor necrosis factor (TNF) pathway, which is sufficient to treat or ameliorate an effect of a polycystic disease. Methods of treating or ameliorating an effect of a polycystic kidney disease (PKD) are also provided. Methods are also provided for identifying a candidate compound that may be effective to treat or ameliorate an effect of a polycystic disease or to increase polycystin-2 (PC2) function or decrease Rab11-Family of Interacting Protein2 (FIP2) function. Further provided are methods for identifying a patient having, or who is at risk for developing, a polycystic disease or who would benefit from treatment with a TNF-alpha inhibitor.