The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. A screen for genes that control Drosophila heart development revealed a cardiac defect in which pericardial and cardial cells dissociate, which causes loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in the genes encoding HMG-CoA reductase, downstream enzymes in the mevalonate pathway, and G protein Gγ1, which is geranylgeranylated, thus representing an end point of isoprenoid biosynthesis. Our findings reveal a cardial cell–autonomous requirement of Gγ1 geranylgeranylation for heart formation and suggest the involvement of the mevalonate pathway in congenital heart disease.