Notes: Summary The developmental properties of three neoplasms found in lethal mutants ofDrosophila melanogaster were studied and compared with the development of the corresponding wild-type organs. Two of these neoplasms are found in the late larval lethal mutant,lethal (2) giant larvae 4 (l(2)gl 4) and its allele,lethal (2) giant larvae (l(2)gl). The third neoplasm occurs in the hemizygous lethal male embryos of the mutantNotch 8 (Df(1)N 8). The mutantsl(2)gl 4 andl(2)gl were shown to possess defects involving imaginal primordia of ectodermal origin, such as the imaginal discs of the adult integument and the imaginal optic primordia in the larval brain. They also have enlarged lymph glands and abnormal gonads, salivary and ring glands. Thel(2)gl 4 andl(2)gl mutations transform the imaginal discs into noninvasive, lethal neoplasms and the imaginal optic primordia in the larval brain into an invasive and lethal neuroblastoma. Both neoplasms were serially subcultured in female adult hosts where they grew rapidly and killed their hosts in 7–14 days. The neoplastic development of thel(2)gl 4 imaginal discs and brain proved autonomous at all stages that were investigated from 10 hour old embryos to mature larvae. When exposed to the hormonal conditions of metamorphosis, the neoplastic tissues,in situ as well as those that had been culturedin vivo, ceased to grow but failed to metamorphose into parts of the adult integument or brain. Furthermore, in almost all cases they failed to resume their growth in the adult fly after metamorphosis. Thel(2)gl 4 brain neuroblastoma changed after prolonged subculturein vivo so that although the cells stopped dividing temporarily at the time of metamorphosis of the host, they resumed their growth shortly thereafter and continued to divide throughout adult development and in the emerged adult. Many of thel(2)gl 4 neuroblastoma cells showed abnormal karyotypes, shapes and sizes after prolonged culturein vivo. Thel(2)gl 4 imaginal disc tissue resembles, in both structure and behavior, certain atelotypic tissue sublines which arise from wild-type imaginal discs after prolonged culturein vivo: the ultrastructure of both types of cells are similar and both cease to grow when exposed to hormonal conditions of metamorphosis. Apparently the epigenetic processes which transform wild-type imaginal discs afterin vivo subculture into atelotypic neoplasms have the same phenotypic expression as the genetic processes at work inl(2)gl 4 imaginal discs. An analysis of several other late larval and larval-pupal mutants with defective imaginal discs, such asl(2)gd andl(1)d.lg.-1 revealed that they also had defects in parts of the brain destined to form adult structures. This observation indicates that mutations that affect imaginal discs of the adult integument also affect the imaginal primordia of the adult brain. The neoplasm in the hemizygous male embryo of the embryonic lethalNotch 8 is a teratoma-like growth which is lethal and invasive; when implanted into female adult hosts it gives rise to a mass of tissue which consists of most cell types present in the larval nervous system and a number of other unidentified cell types. It too can be subculturedin vivo for many transfer generations. The relative infrequency of neoplasms in insects is analyzed and an attempt is made to explain this infrequency and the occurrence of neoplasms in specific tissues of insects at specific developmental stages. Genetic and epigenetic neoplasms ofDrosophila are compared with neoplasms of other insects and of vertebrates and it is concluded that both genetic and epigenetic neoplasms ofDrosophila share the essential features of vertebrate neoplasms.