An earlier study into RNA-mediated gene regulation began in the lab of H. Robert Horvitz at the Massachussetts Institute of Technology and was continued by two of his associates, Victor Ambros and Gary Ruvkun. Two C. elegans genes, lin-4 and let-7, were identified for their roles in developmental timing and sequence, and also were implicated in cancer. Ambros found that instead of encoding a protein, lin-4 encoded a 22nt RNA. In his 1993 paper, he explained that the RNA regulated the activity of another gene, lin-14, by base-pairing to the lin-14 mRNA. Although this endogenous mechanism is similar to RNAi as described in Fire and Mellos 1998 paper, the scientific community at the time believed this phenomenon was limited only to C. elegans.  Seven years after Ambros paper, Ruvkun showed that let-7 regulates other C. elegans genes and noted that let-7 is present in a number of different species.

Research into these endogenous small RNA strands, called microRNAs (miRNA), has increased from 4 publications in 2000 to over 600 in 2006. The function of specific miRNAs in animals and plants have been described, and as of late 2005, approximately 200 genes encoding miRNA had already been discovered in humans and another 250 or more are predicted.