This chapter is a historical overview of the major discoveries of similarities between human and fly genes, circuits, and pathways. The first hint of such a similarity occurred in 1822 with Geoffroy's finding that the order of organs along the dorsal-ventral axis is reversed in arthropods versus vertebrates. Then in 1915 the fly's visual system was found to be organized according the same connectivity rules as the vertebrate one. In 1917 insects and salamanders were found to regenerate similar triplicated limbs under different conditions (surgery or mutation), and in 1976 a theory was proposed to explain why regeneration obeys the same rules in these different taxa. In 1978 the geneticist Ed Lewis his model for the fly's Bithorax Complex, and the genes of this complex were found (in 1984) to contain the same basic homeobox motif. That same motif was also documented for the Hox Complexes of mice, and in 1988 the Hox genes of the mouse were shown to be arranged colinearly on the chromosome with their axial expression domains, precisely as had earlier been shown for the fly. The final proof of human-fly similarity came in 2001 when the genomes of humans and flies were compared.