Unlike other organs, the adult heart has limited regenerative potential owing to the inability of postnatal cardiomyocytes to undergo proliferative growth. As a result, ischemic heart disease continues to be a major cause of morbidity and mortality worldwide. Elucidating the molecular pathways of cardiomyocyte differentiation and proliferation holds great promise for human health. In a recent paper we employed a multidisciplinary approach to identify a novel pathway required for cardiomyocyte growth and differentiation. Starting with the dissection of a new regulatory sequence required for cardiac specific expression, we identified the cognate DNA binding protein as KLF13, a tissue-restricted member of the newly identified KLF family of zinc-finger proteins. We took advantage of the ease in manipulating Xenopus embryos to genetically alter KLF13 levels thus demonstrating a requirement for KLF13 in cardiac progenitor cell proliferation and heart morphogenesis. Furthermore, we combined biochemical approaches with genetic manipulations in Xenopus to show that KLF13 is a GATA4 interacting protein and a genetic modifier of GATA4 function. Cyclin D1 was identified as a direct transcriptional target for KLF13 that may account for the proliferation defects observed in embryos with downregulated KLF13 levels. Thus, tissue-specific regulators of the cell cycle may be potential congenital heart disease causing genes in humans.