The primary sex-determining signal in the nematode C. elegans is the ratio of X chromosomes to sets of autosomes (X/A ratio). As a consequence, males (XO; ratio 0.5) and hermaphrodites (XX; ratio 1.0) possess different doses of X-linked genes. Here we demonstrate that C. elegans compensates for this disparity in gene dose by equalizing the levels of X-specific mRNA transcripts in the two sexes. Moreover, we show that mutations in three autosomal genes disrupt the process of dosage compensation. Reduction in the activity of either dpy-21, dpy-27, or dpy-28 results in the overexpression of X-specific genes, 2- to 3-fold above wild-type levels.