In the early studies of Drosophila, mutations were merely used as "markers" to study the arrangement of genes on chromosomes. The use of mutants to study Drosophila development, as we understand it today was pioneered by Don Poulson. In 1940, he studied the effect of X-chromosomal deletions on embryonic development, and found that lack of Notch results in neural hyperplasia.

Other attempts to understand development by studying mutants followed. The use of genetic mosaics to study "non-autonomy" has its origin in experiments from Alfred H. Sturtevant around 1930, but was rediscovered by Curt Stern in 1968, who used the method to study bristle pattern. He discovered that some genes were affecting a "prepattern", while others were required to respond to this prepattern. Antonio Garcia-Bellido used genetic mosaics to address a different question. He was interested in "lineage analysis", mapping the origin of adult structures to the embryo. The concept of "selector genes" defining compartments was formulated in 1973.

The bithorax mutant, initially identified by Calvin B. Bridges in 1915, was picked up in 1946 by Ed B. Lewis. Again, his initial interest was to understand the chromosome structure of the bithorax complex. In the 1950s and 60s, Lewis discovered a correlation between the chromosomal arrangement of genes in the bithorax complex and the order of segments they affect in the fly. He proposed that each gene in the linear array functions to give a more posterior identity to the segment in which it is expressed.

In 1980, Christiane Nüsslein-Volhard and Eric Wieschaus published the results of a systematic saturation screen for mutations that affect the early patterning of the embryo. The analyses of the mutants lead to a deep insight into early development. The relevant genes were grouped into classes, which act sequentially to subdivide of the embryo into segments. Four years later, the contribution of the mother for early embryonic development was included. The screen was momentous in many ways. First, it turned the attention of the field to embryonic development. Genetic understanding of developmental biology had so far mainly focused on the analysis of adult phenotypes. And second, with the rising field of molecular biology, the genes were characterized and embryonic patterning understood at the molecular level.