Drosophila can look back at a long tradition, which provided many useful tools. The studies of heredity in the lab of Thomas H. Morgan produced a large number of "trick chromosomes": attached X, balancers (suppressors of recombination), deletions, duplications and translocations. At those times, the genetic effects of those chromosomes itself were the subject of interest. Today, these chromosomes are still a useful tool for any handling with flies.

The beginning of molecular biology opened a new field of Drosophila research. In 1969 Joseph G. Gall and Mary-Lou Pardue established in situ hybridization to polytene chromosomes: now genes could be easily mapped to quite precise locations. Michael Akam developed in situ hybridization to tissues, to visualize gene expression, in 1983.

In 1982, Gerald M. Rubin and Allan C. Spradling produced the first transgenic flies, a prerequisite for many follow-up manipulation techniques that are used today: Enhancer trap, protein trap, induction of gene expression by exogenous transcription factors (the UAS-Gal4 system), or the use of site specific recombinases from yeast to induce mitotic clones.