This article presents a novel three-step method for predicting microRNA (miRNA) target genes in *Drosophila melanogaster*. The method combines sequence complementarity, RNA-RNA duplex formation energy, and conservation of target sites in related genomes to identify potential miRNA targets. The authors validate their method using known miRNA targets and apply it to discover hundreds of potential target genes in *D. melanogaster*. The predicted targets are enriched for genes involved in specific developmental stages, cell fate specification, morphogenesis, and nervous system function. The study highlights the role of miRNAs in establishing complex spatial and temporal patterns of gene activity during development and suggests additional roles in the mature organism. The method is also applicable to other genomes with identified miRNA sequences, providing a valuable resource for further research on miRNA regulation.This article presents a novel three-step method for predicting microRNA (miRNA) target genes in *Drosophila melanogaster*. The method combines sequence complementarity, RNA-RNA duplex formation energy, and conservation of target sites in related genomes to identify potential miRNA targets. The authors validate their method using known miRNA targets and apply it to discover hundreds of potential target genes in *D. melanogaster*. The predicted targets are enriched for genes involved in specific developmental stages, cell fate specification, morphogenesis, and nervous system function. The study highlights the role of miRNAs in establishing complex spatial and temporal patterns of gene activity during development and suggests additional roles in the mature organism. The method is also applicable to other genomes with identified miRNA sequences, providing a valuable resource for further research on miRNA regulation.