RNA interference (RNAi) is a conserved silencing mechanism that depends on the generation of small RNA molecules that leads to the degradation of the targeted messenger RNAs (mRNAs). Nuclear RNAi is a unique process that triggers regulation through epigenetic alterations to the genome. This pathway has been extensively characterized in Caenorhabditis elegans and involves the nuclear recruitment of H3K9 histone methyltransferases by the Argonautes HRDE-1 and NRDE-3. The coordinate regulation of genetic targets by H3K9 methylation and the nuclear Argonautes is highly complex and has been mainly described based on the small RNA populations that are involved. Recent studies have also linked the nuclear RNAi pathway to the compaction of the hermaphrodite X chromosomes during dosage compensation (DC), a mechanism that balances genetic differences between the biological sexes by repressing X chromosomes in hermaphrodites. This chromosome-wide process provides an excellent opportunity to further investigate the relationship between H3K9 methylation and the nuclear Argonautes. Our work suggests that the nuclear RNAi and the H3K9 methylation pathways each contribute to the condensation of the X chromosomes during DC but the consequences on the transcriptional output of X-linked genes are minimal. Instead, nuclear RNAi mutants exhibit global transcriptional differences, in which HRDE-1 and NRDE-3 affect expression of their mRNA targets through different relationships to H3K9 methylation.