The embryonic epicardium is an important source of cardiovascular precursor cells and paracrine factors that are required for adequate growth and complete formation of the heart. WT1 is expressed in the embryonic and neonatal heart in mammals; however it becomes quiescent in the adult heart. Recently, a great deal of attention has been given to the signalling pathways regulated by WT1 that promote heart development. It has been demonstrated that WT1 can regulate epicardial EMT and the release of growth factors; however there is little information on the signalling pathways regulated by WT1 that could act in a negative manner. Transcriptome analysis of Wt1KO epicardial cells reveals an unexpected role for WT1 in repressing the expression of interferon-regulated genes that could be involved in a negative regulation of heart morphogenesis. We showed that WT1 is required to repress the expression of the chemokines Ccl5 and Cxcl10 in epicardial cells. We observed an inverse correlation of Wt1 and the expression of Cxcl10 and Ccl5 during epicardium development. Chemokine receptor analyses of hearts from Wt1(gfp/+) mice demonstrate the differential expression of their chemokine receptors in GFP(+) epicardial enriched cells and GFP(-) cells. Functional assays demonstrate that CXCL10 and CCL5 inhibit epicardial cell migration and the proliferation of cardiomyocytes respectively. WT1 regulates the expression levels of Cxcl10 and Ccl5 in epicardial cells directly and indirectly through increasing the levels of IRF7. As epicardial cell reactivation after myocardial damage is linked with WT1 expression, the present work has potential implications in the field of adult heart repair.