Discoveries in fruit flies have greatly contributed to our understanding of neuroscience. The use of an unparalleled wealth of tools, many of which originated between 1910–1960, has enabled milestone discoveries in nervous system development and function. Such findings have triggered and guided many research efforts in vertebrate neuroscience. After 100 years, fruit flies continue to be the choice model system for many neuroscientists. The combinational use of powerful research tools will ensure that this model organism will continue to lead to key discoveries that will impact vertebrate neuroscience.