Extensive programmed rearrangement of DNA, including DNA elimination, chromosome fragmentation, and DNA unscrambling, takes place in the newly developed macronucleus during the sexual reproduction of ciliated protozoa. Recent studies have revealed that two distant classes of ciliates use distinct types of non-coding RNAs to regulate such DNA rearrangement events. DNA elimination in Tetrahymena is regulated by small non-coding RNAs that are produced and utilized in an RNA interference (RNAi)-related process. It has been proposed that the small RNAs produced from the micronuclear genome are used to identify eliminated DNA sequences by whole-genome comparison between the parental macronucleus and the micronucleus. In contrast, DNA unscrambling in Oxytricha is guided by long non-coding RNAs that are produced from the parental macronuclear genome. These long RNAs are proposed to act as templates for the direct unscrambling events that occur in the developing macronucleus. Both cases provide useful examples to study epigenetic chromatin regulation by non-coding RNAs.