neuromancer/Tbx20 (nmr) genes are cardiac T-box transcription factors that are evolutionarily conserved from flies to humans. Along with other known congenital heart disease genes, including tinman/Nkx2–5, dorsocross/Tbx5/6, and pannier/Gata4/6, they are important for specification and morphogenesis of the embryonic heart. The Drosophila heart has proven to be an excellent model to study genes involved in establishing and maintaining the structural integrity of the adult heart, as well as genes involved in maintaining physiological function. Using this model, we have identified nmr as a gene required in adult fly hearts for the maintenance of both normal myofibrillar architecture and cardiac physiology. Moreover, we have discovered synergistic interactions between nmr and other cardiac transcription factors, including tinman/Nkx2–5, in regulating cardiac performance, rhythmicity, and cardiomyocyte structure, reminiscent of similar interactions in mice. This suggests a remarkably conserved role for this network of cardiac transcription factors in the genetic control of the adult heart. In addition, nmr-tinman interactions also influence the expression of potential downstream effectors, such as ion channels. Interestingly, genetic screening of patients with dilated cardiomyopathy and congenital heart disease has revealed TBX20 variants in three sporadic and two familial cases that were not found in controls. These findings suggest that the fly heart might serve as an identifier of candidate genes involved in human heart disease.