It has been known for more than a decade that increasing the gene copy number does not necessarily lead to increased gene activity. Plants have developed efficient mechanisms such as post-transcriptional gene silencing (PTGS) to regulate abnormal gene expression in a sequence-specific fashion. PTGS of (trans)genes can be inhibited by non-homologous viruses, and PTGS-impaired mutants can be hypersensitive to such viruses, indicating that in plants this mechanism is triggered to protect against viral invasion. Genetic analysis of a related phenomenon, quelling, in Neurospora has led to the identification of two genes encoding proteins that share homologies with RNA-dependent RNA polymerases and with DNA helicases. This finding reinforces previous models in which PTGS involves RNA molecules complementary to the RNA species targeted for degradation. Insight into the mechanisms of PTGS may also be obtained in other distant organisms such as Caenorhabditis elegans in which a related phenomenon, RNA interference, has been genetically studied, leading to the identification of two genes encoding proteins sharing homologies with a translation factor and an RNase D.