We have created numerous models of congenital heart disease and cardiomyopathies using the Drosophila heart as a genetic model system. These include models for long-QT cardiac arrhythmias, for dilated and restrictive cardiac disorders, for haplo-insufficiencies and polygenic interactions of transcription factors, exhibiting pronounced aggravation with age, and involving genetic pathways that are conserved from fly to human. For example, insulin/TOR and SREBP signaling, known to modulate growth and (lipid) metabolism in many organisms, can act autonomously within the myocardium to fine-tune cardiac performance that deteriorates with age or due to a high fat diet. Among the new genetic pathways, we discovered to be critical for establishing adult heart function, involve cardiogenic determinants, such as tinman/Nkx2-5, and microRNAs (miR) to control not only cardiac development but also functional properties of the mature heart. In a genetic modifier screen for mutations that cause cardiac dysfunction in a weak tinman mutant, we identified the Rho-GTPase encoded by Cdc42. We found evidence that tinman/Nkx2-5 regulates Cdc42 function via miR-1 in the adult heart of flies as well as mice. This shows that the Drosophila heart serves as an efficient discovery tool for conserved (polygenic) modulators of heart disease. Cdc42 is also critical for cardiac morphogenesis in the embryo, where it functions to control localized non-muscle myosin accumulation at the leading edge of cardiomyocytes during heart tube assembly and lumen formation. We recently also developed a Drosophila model for High Fat Diet-induced (HFD) obesity and heart dysfunction associated with excessive cardiac fat accumulation, involving nutrient-sensitive TOR signaling. In a screen for other modifiers of obesity-associated heart dysfunction, we found a role for the fly homolog of PPAR-γ Coactivator-1 genes, PGC-1/Spargel in protecting the heart from HFD-induced cardiomyopathy: Flies with reduced PGC-1/Spargal function show elevated obesity and exasperated heart dysfunction in response to a HFD, whereas overexpression, even restricted to the heart protects from cardiomyopathy phenotypes. Thus, PGC-1 plays an important role in HFD-induced obesity and heart dysfunction.