The extensive analysis of the impact of segmental aneuploidy by Lindsley et al. (1972) showed that there are relatively few haplo-lethal loci in the genome and that, with one exception, all loci are triplo-viable. The exceptional locus, which lies in salivary gland chromosome region 83D-E, is associated with lethality when present in either one or three doses in an otherwise diploid individual (Denell 1976). The genetic nature of the phenomenon has been studied by examining the rates of induction, by ionizing radiation and chemical mutagens, of mutations affecting the dose-sensitive behavior. For both types of mutagens, the frequency of inactivation of the locus is relatively low, and a high proportion of such mutations is associated with chromosomal deficiencies. These data indicate that the locus is infrequently and perhaps never inactivated by a DNA base-pair substitution and thus that the triplo-lethal phenomenon is not associated with a "typical" structural gene. It is possible that the triplo-lethal locus is very small, is reiterated or otherwise complex or is functionally insensitive to base-pair substitutions. The result that all mutations that complement a duplication of the triplo-lethal locus are lethal in heterozygous combination with a normal third chromosome argues that triplo- and haplo-lethality are concomitants of the same phenomenon. Salivary gland chromosome analysis of newly induced deficiencies and duplications localizes the locus to 83D4,5--83E1,2, and further cytogenetic mapipulation shows that the dose-sensitive behavior is independent of the position of the locus in the genome.