A new paradigm of RNA-directed gene expression regulation has emerged recently, profound in scope but arresting in the apparent simplicity of its core mechanism. Cells express numerous small ( approximately 22 nucleotide) RNAs that act as specificity determinants to direct destruction or translational repression of their mRNA targets. These small RNAs arise from processing of double-stranded RNA by the Dicer nuclease and incorporate with proteins that belong to the Argonaute family. Small RNAs might also target and silence homologous DNA sequences. The immense potential of small RNAs as controllers of gene networks is just beginning to unfold.