Drosophila melanogaster is one of the most widely used model organisms. About 77% of known human disease genes have an ortholog in Drosophila, and many of the cellular signaling pathways are common between fruit flies and mammals. For example, a key signaling pathway in the regulation of growth and metabolism, the insulin/insulin-like growth factor 1 signaling pathway, is well conserved between flies and humans. Downstream effectors of this pathway are the Forkhead box class O (FOXO) family of transcription factors, with four members in mammals and a single FOXO protein in Drosophila, dFOXO. Research in Drosophila has been critical to elucidate the molecular mechanisms by which FOXO transcription factors regulate insulin signaling. In this review, we summarize the studies leading to dFOXO identification and its characterization as a central regulator of metabolism, life span, cell cycle, growth, and stress resistance.