Small noncoding RNAs have emerged as key players in epigenetic regulation. Recently, a novel class of small RNAs that interact with Piwi proteins has been discovered in the mammalian and Drosophila germ line. These Piwi-interacting RNAs (piRNAs) represent a distinct small RNA pathway that is widely thought to function only in the germ line. In this chapter, we review our recent work with our collaborators on the epigenetic function of the Drosophila Piwi protein and its associated piRNAs in somatic cells. This work has revealed a novel epigenetic mechanism mediated by Piwi and its associated piRNAs in somatic cells that might also be applicable to the germ line. On the basis of these results, we propose a "Piwi-piRNA guidance hypothesis" for Piwi/piRNA-mediated epigenetic programming, in which the Piwi-piRNA complex serves as sequence-recognition machinery that recruits epigenetic effectors such as heterochromatin protein 1a (HP1a) to specific sites in the genome to execute epigenetic regulation.