Identifying genetic components is an essential step toward understanding complex developmental processes. The primitive heart of the fruit fly, the dorsal vessel, which is a hemolymph-pumping organ, has provided a unique model system to identify cardiogenic genes and to further our understanding of the molecular mechanisms of cardiogenesis. Using RNA interference in developing Drosophila embryos, we performed a genomewide search for cardiogenic genes. Through analyses of the >5,800 genes that cover Ϸ40% of all predicted Drosophila genes, we identified a variety of genes encoding transcription factors and cell signaling proteins required for different steps during heart development. Analysis of mutant heart phenotypes and identified genes suggests that the Drosophila heart tube is segmentally patterned, like axial patterning, but assembled with regional modules. One of the identified genes, simjang, was further characterized. In the simjang mutant embryo, we found that within each segment a subset of cardial cells is missing. Interestingly, the simjang gene encodes a protein that is a component of the chromatin remodeling complex recruited by methyl-CpG-DNA binding proteins, suggesting that epigenetic information is crucial for specifying cardiac precursors. Together, these studies not only identify key regulators but also reveal mechanisms underlying heart development. O ver the last decade significant progress has been made in our understanding of the molecular details of cardiac morphogenesis. These advances can be attributed to the fact that many embryonic events involved in cardiogenesis are remarkably conserved among distinct species (1-3). In the Drosophila embryo, bilaterally symmetric groups of cardiac precursor cells in the dorsal-most mesoderm, specified by positional information provided by intrinsic cell-autonomous factors and extrinsic signals, meet in the dorsal midline to form a linear heart tube (3). Unlike the vertebrate linear heart tube, which proceeds further to looping and multichamber formation, the Drosophila heart remains a contractile linear tube at maturity. Two major classes of cell observed within the Drosophila cardiogenic repertoire are cardial cells (cardioblasts), which form the lumen of the linear heart tube, and pericardial cells, which flank and are associated with cardial cells (4). Cardial cells eventually form the cardiac muscles and are the contractile cells of the heart, whereas pericardial cells do not express muscle proteins but may function in hemolymph filtration. The linear heart tube shows clear structural differences along its length after its formation in late embryogenesis. The posterior three segments constitute the heart, a contractile tube with a wide bore involved in the forward pumping of hemolymph. Three pairs of specialized inflow valves (ostia) are present in the heart to facilitate the lateral entry of hemolymph (5, 6). Anterior to the heart is a narrower section, termed the aorta, that encompasses four segments. Despite its apparently simple structure an...