In 1990, the first indication for the existence of nucleic acid sequence guided gene silencing came from scientists who were introducing additional copies of a gene responsible for the darkening of flower color into the Petunia genome. In addition to creating darker flowers, the insertion of multiple copies of the gene created white flowers or flowers with patches of white mixed with patches of color (variegated). The white and variegated plants had recognized the newly introduced transgenes as foreign and marked them as well as the endogenous homologous gene for silencing—a process that became known as cosuppression.

Subsequent experiments showed that ribonucleic acid (RNA) transcribed from the transgenes was the silencing trigger. Andrew Fire and colleagues discovered in 1998 that injection of double-stranded RNA (dsRNA) into the nematode worm Caenorhabditis elegans caused sequence-specific degradation of cytoplasmic messenger RNAs (mRNAs) containing the same sequence as the dsRNA trigger. This phenomenon was termed RNA interference (RNAi), and was soon related to the cosuppression events described earlier in plants.