RNA interference or RNAi was first discovered as an experimental approach that induces potent sequence-specific gene silencing. Remarkably, subsequent studies on dissecting the molecular mechanism of the RNAi pathway reveal that RNAi is conserved in most eukaryotes. In addition, genes and mechanisms related to RNAi are employed to elicit the regulation of endogenous gene expression that controls a variety of important biological processes. To investigate the mechanism of RNAi in the nematode C. elegans, we performed genetic screens in search of RNAi deficient mutants (rde). Here I report the summary of the genetic screens in search of rde mutants as well as the identification of two novel genes required for the RNAi pathway, rde-3 and rde-8. In addition, we demonstrate that some of the rde genes, when mutated, render the animals developmentally defective, suggesting that these rde genes also function in developmental gene regulation. This work presents novel insights on the components of the RNAi pathway and the requirement of these components in the regulation of endogenous gene expression.