Several classes of non-protein-coding RNAs have recently been identified as epigenetic regulators of developmental genome rearrangements in ciliates, providing an interesting insight into the role of genome-wide transcription. In these unicellular eukaryotes, extensive rearrangements of the germline genome occur during the development of a new somatic macronucleus from the germline micronucleus. Rearrangement patterns are not dictated by the germline sequence, but reproduce the pre-existing rearrangements of the maternal somatic genome, implying a homology-dependent global comparison of germline and somatic genomes. We review recent evidence showing that this is achieved by a natural genomic subtraction, computed by pairing interactions between meiosis-specific, germline scnRNAs (small RNAs that resemble metazoan piRNAs) and longer non-coding transcripts from the somatic genome. We focus on current models for the RNA-based mechanisms enabling the cell to recognize the germline sequences to be eliminated from the somatic genome and to maintain an epigenetic memory of rearrangement patterns across sexual generations.