Ciliated protozoa undergo extensive DNA rearrangements, including DNA elimination, chromosome breakage and DNA unscrambling, when the germline micronucleus produces the new macronucleus during sexual reproduction. It has long been known that many of these events are epigenetically controlled by DNA sequences of the parental macronuclear genome. Recent studies in some model ciliates have revealed that these epigenetic regulations are mediated by non-coding RNAs. DNA elimination in Paramecium and Tetrahymena is regulated by small RNAs that are produced and operated by an RNAi (RNA interference)-related mechanism. It has been proposed that the small RNAs from the micronuclear genome can be used to identify eliminated DNAs by whole-genome comparison of the parental macronucleus and the micronucleus. In contrast, DNA unscrambling in Oxytricha is guided by long non-coding RNAs that are produced from the somatic parental macronuclear genome. These RNAs are proposed to act as templates for the direct unscrambling events that occur in the developing macronucleus. The possible evolutionary benefits of these RNA-directed epigenetic regulations of DNA rearrangement in ciliates are discussed in the present chapter.