Abstract Drosophila sex is determined by the action of the X:A chromosome balance on transcription of Sex-lethal (Sxl), a feminizing switch gene. We obtained loss-of-function mutations in denominator elements of the X:A signal by selecting for dominant suppressors of a female-specific lethal mutation in the numerator element, sisterlessA (sisA). Ten suppressors were recovered in this extensive genome-wide selection. All were mutations in deadpan (dpn), a pleiotropic locus previously discovered to be a denominator element. Detailed genetic and molecular characterization is presented of this diverse set of new dpn alleles including their effects on Sxl. Although selected only for impairment of sex-specific functions, all were also impaired in nonsex-specific functions. Male-lethal effects were anticipated for mutations in a major denominator element, but we found that viability of males lacking dpn function was reduced no more than 50% relative to their dpn- sisters. Moreover, loss of dpn activity in males caused only a modest derepression of the Sxl "establishment" promoter (Sxlpe), the X:A target. By itself, dpn cannot account for the masculinizing effect of increased autosomal ploidy, the effect that gave rise to the concept of the X:A ratio; nevertheless, if there are other denominator elements, our results suggest that their individual contributions to the sex-determination signal are even less than that of dpn. The time course of expression of dpn and of Sxl in dpn mutant backgrounds suggests that dpn is required for sex determination only during the later stages of X:A signaling in males to prevent inappropriate expression of Sxlpe in the face of increasing sis gene product levels.